Novel lapachone compounds and methods of use thereof

ABSTRACT

The present invention provides novel tricyclic spiro-oxathiine naphthoquinone derivatives, a synthetic method for making the derivatives, and the use of the derivatives to induce cell death and/or to inhibit proliferation of cancer or precancerous cells. The naphthoquinone derivatives of the present invention are related to the compound known as β-lapachone (3,4-dihydro-2,2-dimethyl-2H-naphtho(1,2-b)pyran-5,6-dione).

BACKGROUND OF THE INVENTION

β-lapachone (3,4-dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione),a quinone, is derived from lapachol (a naphthoquinone) which can beisolated from the lapacho tree (Tabebuia avellanedae), a member of thecatalpa family (Bignoniaceae). Lapachol and β-lapachone (with numbering)have the following chemical structures:

β-lapachone, as well as its intermediates, derivatives and analogsthereof, are described in Li, C. J. et al., (1993) J. Biol. Chem.,268(30): 22463-22468. As a single agent, β-lapachone has demonstratedsignificant antineoplastic activity against human cancer cell lines atconcentrations typically in the range of 1-10 μM (IC₅₀). Cytotoxicityhas been demonstrated in transformed cell lines derived from patientswith promyelocytic leukemia (Planchon et al., (1996) Cancer Res., 55:3706-3711), prostate (Li, C. J., et al., (1995) Cancer Res., 55:3712-3715), malignant glioma (Weller, M. et al., (1997) Int. J. Cancer,73: 707-714), hepatoma (Lai, C. C., et al., (1998) Histol Histopathol,13: 89-97), colon (Huang, L., et al., (1999) Mol Med, 5,: 711-720),breast (Wuertzberger, S. M., et al., (1998) Cancer Res., 58: 1876),ovarian (Li, C. J. et al., (1999) Proc. Natl. Acad. Sci. USA, 96(23):13369-13374), pancreatic (Li, Y., et al., (2000) Mol Med, 6: 1008-1015;Li, Y., (1999) Mol Med, 5: 232-239), and multiple myeloma cell lines,including drug-resistant lines (Li, Y., (2000) Mol Med, 6: 1008-1015).No cytotoxic effects were observed on normal fresh or proliferatinghuman PBMC (Li, Y., (2000) Mol Med, 6:1008-1015).

β-lapachone appears to work by activating DNA damage response/checkpointpathways, which may involve unscheduled expression of checkpointmolecules, e.g. E2F1, independent of DNA damage and cell cycle stages.Several studies have shown that β-lapachone activates checkpointpathways and induces cell death in cancer cells from a variety oftissues without cell death of normal cells from these tissues (U.S.Patent Application Publication No. 2002/0169135, incorporated byreference herein). In normal cells with their intact regulatorymechanisms, such an imposed expression of a checkpoint molecule resultsin a transient expression pattern and causes little consequence. Incontrast, cancer and pre-cancer cells have defective mechanisms, whichresult in unchecked and persistent expression of unscheduled checkpointmolecules, e.g. E2F1, leading to selective cell death in cancer andpre-cancer cells.

In addition to β-lapachone, a number of β-lapachone analogs havingantiproliferative properties have been disclosed in the art, such asthose described in PCT International Application PCT/US93/07878(WO94/04145), which is incorporated by reference herein, and U.S. Pat.No. 6,245,807, incorporated by reference herein, in which a variety ofsubstituents may be attached at positions 3- and 4-on the β-lapachonecompound. PCT International Application PCT/US00/10169 (WO 00/61142),incorporated by reference herein, discloses β-lapachone, which may havea variety of substituents at the 3-position as well as in place of themethyl groups attached at the 2-position. U.S. Pat. Nos. 5,763,625,5,824,700, and 5,969,163, each of which is incorporated by referenceherein, disclose analogs and derivatives with a variety of substituentsat the 2-, 3- and 4-positions. Furthermore, a number of journals reportβ-lapachone analogs and derivatives with substitutents at one or more ofthe following positions: 2-, 3-, 8- and/or 9-positions, (See, Sabba etal., (1984) J Med Chem 27:990-994 (substituents at the 2-, 8- and9-positions); (Portela and Stoppani, (1996) Biochem Pharm 51:275-283(substituents at the 2- and 9-positions); Goncalves et al., (1998)Molecular and Biochemical Parasitology 1:167-176 (substituents at the 2-and 3-positions)).

Moreover, U.S. Patent Application Publication No. 2004/0266857 and PCTIntentional Application PCT/US2003/037219 (WO 04/045557), incorporatedin by reference herein, disclose and several journal reports describestructures having sulfur-containing hetero-rings in the “α” and “β”positions of lapachone (Kurokawa S, (1970) Bulletin of The ChemicalSociety of Japan 43:1454-1459; Tapia, R A et al., (2000) Heterocycles53(3):585-598; Tapia, R A et al., (1997) Tetrahedron Letters38(1):153-154; Chuang, C P et al., (1996) Heterocycles 40(10):2215-2221;Suginome H et al., (1993) Journal of the Chemical Society, ChemicalCommunications 9:807-809; Tonholo J et al., (1988) Journal of theBrazilian Chemical Society 9(2):163-169; and Krapcho A P et al., (1990)Journal of Medicinal Chemistry 33(9):2651-2655).

The references cited herein are not admitted to be prior art to theclaimed invention.

SUMMARY OF THE INVENTION

The present invention provides a compound of Formula I:

or a pharmaceutically acceptable salt and/or an individual diastereomerthereof,

wherein:

X═N-J₁,

O, or S;

p=0, 1 or 2;

q=p or p+1, provided that if p is 0, q does not equal p;

R₁, R₂, R₃, and R₄, are each, independently, H, OH, F, Cl, Br, I, CH₃,CF₃, C₂-C₆ straight chain alkyl, substituted C₁-C₆ straight chain alkyl,C₃-C₆ branched alkyl, C₃-C₈ cycloalkyl, allyl, C₂-C₆ straight chainalkenyl, substituted C₂-C₆ straight chain alkenyl, C₃-C₆ branchedalkenyl, C₅-C₈ cycloalkenyl, C₂-C₆ alkynyl, NO₂, CN, NH₂, alkylamine,substituted alkylamine, dialkylamine, arylamine, C(O)NHR₁₄, NHC(O)R₁₅,carbamoyl, aminesulfoxide, sulfonamide, sulfamoyl, sulfonic acid,phenyl, C₅-C₈ aryl, heteroaryl, heterocyclyl, OCH₃, OCF₃, C₂-C₆ alkoxy,alkoxycarbonyl, carboxyacid, carbonylalkoxy, SH, thioalkyl, thioaryl,alkylthioaryl, or C₁-C₆ hydroxyl alkyl;

J₁ is —(CR₅R₆)_(n)—(CR₇R₈)_(m)—Y, —S(O)_(o)-Z, amidine, substitutedamidine, heterocyclyl, substituted heterocyclyl,3,4-dioxo-3,4-dihydronaphthalenyl, heteroaryl, substituted heteroaryl,

or

m=0, 1, 2, 3, 4, or 5;

n=0, 1, 2, 3, 4, or 5;

o=1 or 2;

t=1 or 2;

R₅ and R₆ are each, independently, H, OH, CH₃, CF₃, C₂-C₆ straight chainalkyl, C₃-C₆ branched alkyl, C₃-C₈ cycloalkyl, allyl, C₂-C₆ straightchain alkenyl, C₃-C₆ branched alkenyl, C₅-C₈ cycloalkenyl, C₂-C₆alkynyl, phenyl, C₅-C₈ aryl, heteroaryl, heterocyclyl, carboxylate, orcarbonylalkoxy; when R₅=R₆, R₅ cannot be OH, NH₂, SH, or NO₂;

R₇ and R₈ are each, independently, H, F, Cl, Br, I, OH, CH₃, C₂-C₆straight chain alkyl, CF₃, C₃-C₆ branched alkyl, C₃-C₈ cycloalkyl, C₂-C₆alkoxy, allyl, C₂-C₆ straight chain alkenyl, C₃-C₆ branched alkenyl,C₅-C₈ cycloalkenyl, C₂-C₆ alkynyl, NO₂, CN, amine, alkylamine,dialkylamine, arylamine, carbamoyl, aminesulfoxide, sulfonamide,sulfonic acid, phenyl, C₅-C₈ aryl, heteroaryl, heterocyclyl, OCH₃, OCF₃,alkoxycarbonyl, carboxyacid, carbonylalkoxy, SH, thioalkyl, thioaryl, oralkylthioaryl; when R₇=R₈, R₇ is not OH, NH₂, SH, or NO₂;

Y is H, F, Cl, Br, I, CR₁₀═CHR₁₁, CF₃, CH₃, C₂-C₆ straight chain alkyl,substituted C₂-C₆ straight chain alkyl, C₃-C₆ branched alkyl, CH₂OR₁₆,phenyl, substituted phenyl, C₅-C₈ aryl, substituted C₅-C₈ aryl, C₃-C₈cycloalkyl, substituted C₃-C₈ cycloalkyl, CH₂-heterocycle, C₅-C₈cycloalkenyl, aryloxy, substituted aryloxy, heteroaryl, substitutedheteroaryl, heterocyclyl, substituted heterocyclyl, benzyl, alkylamine,substituted alkylamine, benzylamine, OH, CH₃, CF₃, OCR₁₂═CHR₁₃, C₂-C₆alkynyl, amine, dialkylamine, arylamine, amide, carbamoyl,aminesulfoxide, sulfamide, sulfamoyl, sulfonic acid, heteroaryloxy,OCH₃, OCF₃, C₂-C₆ alkoxy, alkenoxy, phenoxy, benzyloxy, alkoxycarbonyl,carboxyacid, carboxyalkoxy, carbonylalkyl, thio, alkylthio, thioalkyl,arylthio, thioaryl, alkylthioaryl, or

provided that, when n=0 and m=0, Y is H, heterocyclyl, heteroaryl, C₃-C₈cycloalkyl, C₅-C₈ cycloalkyl, aryl, or

each of which may be substituted; if m=n=o, Y is not

W is C₂-C₆ straight chain alkyl, substituted C₁-C₆ straight chain alkyl,OCH₃, C₂-C₆ alkoxy, alkylthioalkyl, substituted alkylthioalkyl, C₃-C₈cycloalkyl, substituted C₃-C₈ cycloalkyl, C₅-C₈ aryl, substituted aryl,phenyl, substituted phenyl, CR₁₀ ═CHR₁₁, alkylthio, benzyl, substitutedbenzyl, heterocyclyl, substituted heterocyclyl, phenoxy, aryloxy,substituted aryloxy, OCR₁₂═CHR₁₃, benzyloxy, heteroaryloxy, substitutedheteroaryloxy, amine, substituted amine, arylamine, substitutedarylamine, phenylamine, substituted phenylamine, CH₃, CF₃, C₃-C₆branched alkyl, C₅-C₈ cycloalkenyl, C₂-C₆ alkynyl, alkylamine,dialkylamine, heteroaryl, CH₂-heterocyclyl, CH₂-substitutedheterocyclyl, OCF₃, alkenoxy, CH₂OR₁₆, thioalkyl, arylthio, thioaryl,alkylthioaryl or alkylcarboxy, phenyl sulfonylamide, or substituted arylsulfonylamide, chlorophenylacetyl;

Z is CH₃, CF₃, C₂-C₆ straight chain alkyl, heteroaryl, substitutedheteroaryl, phenyl, substituted phenyl, C₅-C₈ aryl, substituted C₅-C₈aryl, C₃-C₆ branched alkyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₂-C₆alkynyl, amine, alkylamine, dialkylamine, arylamine, benzyl,heteroaryloxy, heterocyclyl, CH₂-heterocycle, OCH₃, OCF₃, C₂-C₆ alkoxy,alkenoxy, phenoxy, aryloxy or benzyloxy;

R₉ is H, CH₃, C₂-C₆ straight chain alkyl, or C₃-C₆ branched alkyl;

R₁₀, R₁₁, R₁₂, and R₁₃ are each, independently, H, phenyl, C₅-C₈ aryl,CH₃, CF₃, C₂-C₆ straight chain alkyl, C₃-C₈ cycloalkyl, heteroaryl, orheterocyclyl;

R₁₄ and R₁₅ are each, independently H, C₂-C₆ straight alkyl, C₃-C₆branched alkyl, C₃-C₈ cycloalkyl, allyl, C₂-C₆ straight alkenyl,branched alkenyl, C₅-C₈ cycloalkenyl, phenyl, C₅-C₈ aryl, benzyl,CH₂C(OCH₃)₂, heteroaryl, or heterocyclyl; and,

R₁₆ is C₃-C₆ branched alkyl, C₅-C₈ aryl, substituted C₅-C₈ aryl,heteroaryl, phenyl, substituted phenyl, CH₂-aryl, benzyl, H, CH₃, CF₃,C₂-C₆ straight chain alkyl, C₃-C₈ cycloalkyl, heterocyclyl, orCH₂-heteroaryl.

J₂ and J₃ are each, independently, H, F, Cl, Br, I, CR₁₇═CHR₁₈, CF₃,CH₃, C₂-C₆ straight chain alkyl, substituted C₁-C₆ straight chain alkyl,C₃-C₆ branched alkyl, CH₂OR₂₁, phenyl, C₅-C₈ aryl, substituted C₅-C₈aryl, C₃-C₈ cycloalkyl, substituted C₃-C₈ cycloalkyl, CH₂-heterocycle,C₅-C₈ cycloalkenyl, aryloxy, substituted aryloxy, heteroaryl,substituted heteroaryl, heterocyclyl, substituted heterocyclyl, benzyl,alkylamine, substituted alkylamine, benzylamine, OH, CH₃, CF₃,OCR₁₉═CHR₂₀, C₂-C₆ alkynyl, amine, dialkylamine, arylamine, amide,carbamoyl, aminesulfoxide, sulfamide, sulfamoyl, sulfonic acid,heteroaryloxy, OCH₃, OCF₃, C₂-C₆ alkoxy, alkenoxy, phenoxy, benzyloxy,alkoxycarbonyl, carboxyacid, carboxyalkoxy, carbonylalkyl, thio,alkylthio, thioalkyl, arylthio, thioaryl, alkylthioaryl, or

when J₂=J₃, J₂ is not OH, NH₂, SH, or NO₂; J₂ and J₃ can form a 4, 5; 6,7, 8 membered spiro ring containing 0, 1, or 2 heteroatoms such as O, N,S;

R₁₇, R₁₈, R₁₉, and R₂₀ are each, independently, H, phenyl, C₅-C₈ aryl,CH₃, CF₃, C₂-C₆ straight chain alkyl, C₃-C₈ cycloalkyl, heteroaryl, orheterocyclyl;

R₂₁ is H, C₂-C₆ straight alkyl, C₃-C₆ branched alkyl, C₃-C₈ cycloalkyl,allyl, C₂-C₆ straight alkenyl, branched alkenyl, C₅-C₈ cycloalkenyl,phenyl, C₅-C₈ aryl, benzyl, CH₂C(OCH₃)₂, heteroaryl, or heterocyclyl.

In an embodiment, p=1 and q=1. In another embodiment, p=1 and q=2. Inanother embodiment, p=2 and q=2. In another embodiment, p=2 and q=3. Inanother embodiment, p=0 and q=1.

In an embodiment, R₁, R₂, R₃, and R₄ are each, independently, H, OH, F,Cl, Br, I, CH₃, CF₃, OCH₃, C₂-C₆ alkoxy, C₂-C₆ straight chain alkyl,substituted C₂-C₆ straight chain alkyl, phenyl, C₅-C₈ aryl, NO₂, CN,C(O)NHR₁₄ or NHC(O)R₁₅. In a further embodiment, R₁, R₂, R₃, and R₄ areeach, independently, H, OH, F, Cl, Br, I, CH₃, CF₃, OCH₃, C₂-C₆ alkoxy.In an even further embodiment, R₁, R₂, R₃, and R₄ are each,independently, H or OCH₃. In an even further embodiment, R₁, R₂ and R₄are each H and R₃ is OCH₃.

In an embodiment, X═O or S. In another embodiment

In another embodiment, X═N-J₁.

In an embodiment, J₁ is —(CR₅R₆)_(n)—(CR₇R₈)_(m)—Y.

In an embodiment, n=0 and m=0. In another embodiment, n=1 and m=0. Inanother embodiment, n=1 and m=1. In another embodiment, n=1 and m=2. Inanother embodiment, n=5 and m=5.

In an embodiment, R₅ and R₆ are each, independently, H or CH₃.

In an embodiment, R₇ and R₈ are each, independently, H, F, Cl, Br, I,OH, CH₃, C₂-C₆ straight chain alkyl, CF₃, C₃-C₆ branched alkyl, C₃-C₈cycloalkyl, or C₂-C₆ alkoxy. In a further embodiment, R₇ and R₈ areeach, independently, H or OH.

In an embodiment, Y is CH₂OR₁₆, phenyl, substituted C₅-C₈ aryl orbenzyl.

In an embodiment, R₅ and R₆ are each H. In a further embodiment, Y issubstituted or unsubstituted C₅-C₈ aryl. In an even further embodiment,the substituted C₅-C₈ aryl is substituted with from 1 to 5 substituentseach of which is independently CN, Cl or F.

In an embodiment, R₅ and R₆ are each H and R₇ and R₈ are each,independently, H or OH. In a further embodiment, Y is CH₂OR₁₆. In afurther embodiment, R₁₆ is substituted or unsubstituted C₅-C₈ aryl. Inan even further embodiment, the substituted C₅-C₈ aryl is substitutedwith from 1 to 5 substituents each of which is independently C₃-C₆branched alkyl, Cl, or F.

In an embodiment, J₁ is —S(O)_(o)-Z. In a further embodiment, o=1. In analternative embodiment, o=2. In an embodiment, Z is CH₃, CF₃, C₂-C₆straight chain alkyl, heteroaryl, substituted heteroaryl, phenyl,substituted phenyl, C₅-C₈ aryl, or substituted C₅-C₈ aryl.

In an embodiment, J₁ is

In an embodiment, t=1. In a further embodiment, W is substituted aryl,phenyl, phenoxy, aryloxy and substituted aryloxy. In an even furtherembodiment, the aryl and aryloxy is substituted with from 1 to 5substituents each of which is independently CF3 or F.

In an alternative embodiment, t=2. In a further embodiment, t=2 and W isC₂-C₆ alkoxy.

In an embodiment, R₉ is H.

In an embodiment, R₁₀ and R₁₁ are both H.

In an embodiment, R₁₂ and R₁₃ are both H.

In an embodiment, R₁₂ is H and R₁₃ is phenyl.

In an embodiment, R₁₆ is C₃-C₆ branched alkyl, C₅-C₈ aryl, substitutedC₅-C₈ aryl, heteroaryl, phenyl, substituted phenyl, CH₂-aryl, or benzyl.

In an embodiment, the compound of the present invention is selected fromthe following compounds, or a pharmaceutically acceptable salt and/or anindividual diastereomer thereof:

-   1′-(3-chlorobenzoyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 55);-   1′-(3,4-dichlorobenzoyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 53);-   4-[(5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-yl)methyl]benzonitrile    (Compound 123);-   1′-(2-phenylethyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 155);-   1′-(4-fluorobenzyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 125);-   1′-[3-(4-tert-butylphenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 157);-   1′-(2-hydroxy-3-phenylpropyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 163);-   3-(trifluoromethyl)phenyl    5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylate    (Compound 96);-   4-fluorophenyl    5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylate    (Compound 97);-   1′-(2-chloro-6-fluorobenzyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 129);-   1′-(3-chloro-4-fluorobenzyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 142);-   1′-(3-phenoxypropyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 144);-   1′-[2-(4-chlorophenoxy)ethyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 145);-   1′-[(2S)-3-(4-fluorophenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 180);-   1′-[(2S)-3-(4-tert-butylphenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 184);-   1′-[(2R)-3-(4-tert-butylphenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 185);-   1′-[(2R)-3-(4-fluorophenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 181);-   1′-[(2S)-3-(4-chlorophenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 182);-   1′-[(2R)-3-(4-chlorophenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 183);-   1′-[(2R)-2-hydroxy-3-phenylpropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 186);-   1′-[(2S)-2-hydroxy-3-phenylpropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 187);-   1′-[(2S)-2-hydroxy-3-(2-methylphenoxy)propyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 200);-   1′-isopropylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 152);-   1′-[(2S)-3-(4-ethylphenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 207);-   1′-[(2R)-3-(4-ethylphenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 228);-   1′-[(2R)-2-hydroxy-3-(2-methylphenoxy)propyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 224).

The present invention also provides a pharmaceutical composition thatcomprises a compound of Formula I in combination with a pharmaceuticallyacceptable carrier or excipient. In an embodiment, the pharmaceuticalcomposition further comprises a second chemotherapeutic agent. In afurther embodiment, said second chemotherapeutic agent is selected fromthe group consisting of tamoxifen, raloxifene, anastrozole, exemestane,letrozole, cisplatin, carboplatin, paclitaxel, cyclophosphamide,lovastatin, minosine, gemcitabine, araC, 5-fluorouracil, methotrexate,docetaxel, goserelin, vincristin, vinblastin, nocodazole, teniposide,etoposide, epothilone, navelbine, camptothecin, daunonibicin,dactinomycin, mitoxantrone, amsacrine, doxorubicin, epirubicin,idarubicin imatanib, gefitinib, erlotinib, sorafenib, sunitinib malate,trastuzumab, rituximab, cetuximab, and bevacizumab.

The present invention further provides a method of treating a cellproliferative disorder. The method comprises administering to a subjectin need thereof a therapeutically effective amount of a compound offormula I as defined in claim 1, or a pharmaceutically acceptable saltthereof, or a prodrug or metabolite thereof, in combination with apharmaceutically acceptable carrier, wherein said cell proliferativedisorder is treated.

In an embodiment, the cell proliferative disorder is a precancerouscondition.

In another embodiment, the cell proliferative disorder is a cancer. Inan embodiment, the cancer is adenocarcinoma, squamous carcinoma,sarcoma, lymphoma, multiple myeloma, or leukemia. In a furtherembodiment, the cancer is lung cancer, colon cancer, breast cancer,pancreatic cancer, prostate cancer, acute leukemia, chronic leukemia,multiple melanoma, ovarian cancer, malignant glioma, leiomyosarcoma,hepatoma, or head and neck cancer.

In an embodiment, the compound of formula I or a pharmaceuticallyacceptable salt thereof, or a prodrug or metabolite thereof, isadministered in combination with a second chemotherapeutic agent. In afurther embodiment, the second chemotherapeutic agent is selected fromthe group consisting of tamoxifen, raloxifene, anastrozole, exemestane,letrozole, cisplatin, carboplatin, paclitaxel, cyclophosphamide,lovastatin, minosine, gemcitabine, araC, 5-fluorouracil, methotrexate,docetaxel, goserelin, vincristin, vinblastin, nocodazole, teniposide,etoposide, epothilone, navelbine, camptothecin, daunonibicin,dactinomycin, mitoxantrone, amsacrine, doxorubicin, epirubicin,idarubicin imatanib, gefitinib, erlotinib, sorafenib, sunitinib malate,trastuzumab, rituximab, cetuximab, and bevacizumab.

In an embodiment, the treating cancer comprises a reduction in tumorsize, a delay of tumor growth, an improvement in the survival ofpatients, or an improvement in the quality of patient life, or at leasttwo of the above.

In another embodiment, the cancer is primary cancer or metastaticcancer, or both.

Other features and advantages of the present invention are apparent fromthe additional descriptions provided herein including the differentexamples. The provided examples illustrate different components andmethodology useful in practicing the present invention. The examples donot limit the claimed invention. Based on the present disclosure theskilled artisan can identify and employ other components and methodologyuseful for practicing the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows that the treatments with the test compounds reduced themean tumor volume of human colon cancer xenograft.

FIG. 1A shows the treatment with Compound 184

FIG. 1B shows the treatments with Compound 186 and Compound 187

FIG. 1C shows the treatment with Compound 182

FIG. 1D shows the treatments with Compound 180 and Compound 125

DETAILED DESCRIPTION OF THE INVENTION 1. The Lapachone Compounds

The present invention provides novel tricyclic spiro-oxathiinenaphthoquinone derivatives, a synthetic method for making thederivatives, and the use of the derivatives to inhibit proliferationand/or inducing cell death of neoplastic cells. The naphthoquinonederivatives of the present invention are related to the compounds knownas β-lapachone(3,4-dihydro-2,2-dimethyl-2H-naphtho(1,2-b)pyran-5,6-dione). Thestructure of β-lapachone is described above.

The β-lapachone analogs of the present invention include spiro-oxathiinehetero-rings. There are no known naphthoquinone derivatives that havedihydrospiro-oxathiine hetero-rings in the “β” position, i.e. analogousto the positioning for the tetrahydropyran ring in β-lapachone.

In one embodiment, the present invention provides the compounds ofFormula I:

or a pharmaceutically acceptable salt and/or an individual diastereomerthereof,

wherein:

X═N-J₁,

O, or S;

p=0, 1 or 2;

q=p or p+1, provided that if p is 0, q does not equal p;

R₁, R₂, R₃, and R₄, are each, independently, H, OH, F, Cl, Br, I, CH₃,CF₃, C₂-C₆ straight chain alkyl, substituted C₁-C₆ straight chain alkyl,C₃-C₆ branched alkyl, C₃-C₈ cycloalkyl, allyl, C₂-C₆ straight chainalkenyl, substituted C₂-C₆ straight chain alkenyl, C₃-C₆ branchedalkenyl, C₅-C₈ cycloalkenyl, C₂-C₆ alkynyl, NO₂, CN, NH₂, alkylamine,substituted alkylamine, dialkylamine, arylamine, C(O)NHR₁₄, NHC(O)R₁₅,carbamoyl, aminesulfoxide, sulfonamide, sulfamoyl, sulfonic acid,phenyl, C₅-C₈ aryl, heteroaryl, heterocyclyl, OCH₃, OCF₃, C₂-C₆ alkoxy,alkoxycarbonyl, carboxyacid, carbonylalkoxy, SH, thioalkyl, thioaryl,alkylthioaryl, or C₁-C₆ hydroxyl alkyl;

J₁ is —(CR₅R₆)_(n)—(CR₇R₈)_(m), —Y, —S(O)_(o)-Z, amidine, substitutedamidine, heterocyclyl, substituted heterocyclyl,3,4-dioxo-3,4-dihydronaphthalenyl, heteroaryl, substituted heteroaryl,

or

m=0, 1, 2, 3, 4, or 5;

n=0, 1, 2, 3, 4, or 5;

o=1 or 2;

t=1 or 2;

R₅ and R₆ are each, independently, H, OH, CH₃, CF₃, C₂-C₆ straight chainalkyl, C₃-C₆ branched alkyl, C₃-C₈ cycloalkyl, allyl, C₂-C₆ straightchain alkenyl, C₃-C₆ branched alkenyl, C₅-C₈ cycloalkenyl, C₂-C₆alkynyl, phenyl, C₅-C₈ aryl, heteroaryl, heterocyclyl, carboxylate, orcarbonylalkoxy; when R₅=R₆, R₅ cannot be OH, NH₂, SH, or NO₂;

R₇ and R₈ are each, independently, H, F, Cl, Br, I, OH, CH₃, C₂-C₆straight chain alkyl, CF₃, C₃-C₆ branched alkyl, C₃-C₈ cycloalkyl, C₂-C₆alkoxy, allyl, C₂-C₆ straight chain alkenyl, C₃-C₆ branched alkenyl,C₅-C₈ cycloalkenyl, C₂-C₆ alkynyl, NO₂, CN, amine, alkylamine,dialkylamine, arylamine, carbamoyl, aminesulfoxide, sulfonamide,sulfonic acid, phenyl, C₅-C₈ aryl, heteroaryl, heterocyclyl, OCH₃, OCF₃,alkoxycarbonyl, carboxyacid, carbonylalkoxy, SH, thioalkyl, thioaryl, oralkylthioaryl; when R₇=R₈, R₇ is not OH, NH₂, SH, or NO₂;

Y is H, F, Cl, Br, I, CR₁₀═CHR₁₁, CF₃, CH₃, C₂-C₆ straight chain alkyl,substituted C₂-C₆ straight chain alkyl, C₃-C₆ branched alkyl, CH₂OR₁₆,phenyl, substituted phenyl, C₅-C₈ aryl, substituted C₅-C₈ aryl, C₃-C₈cycloalkyl, substituted C₃-C₈ cycloalkyl, CH₂-heterocycle, C₅-C₈cycloalkenyl, aryloxy, substituted aryloxy, heteroaryl, substitutedheteroaryl, heterocyclyl, substituted heterocyclyl, benzyl, alkylamine,substituted alkylamine, benzylamine, OH, CH₃, CF₃, OCR₁₂═CHR₁₃, C₂-C₆alkynyl, amine, dialkylamine, arylamine, amide, carbamoyl,aminesulfoxide, sulfamide, sulfamoyl, sulfonic acid, heteroaryloxy,OCH₃, OCF₃, C₂-C₆ alkoxy, alkenoxy, phenoxy, benzyloxy, alkoxycarbonyl,carboxyacid, carboxyalkoxy, carbonylalkyl, thio, alkylthio, thioalkyl,arylthio, thioaryl, alkylthioaryl, or

provided that, when n=0 and m=0, Y is H, heterocyclyl, heteroaryl, C₃-C₈cycloalkyl, C₅-C₈ cycloalkyl, aryl, or

each of which may be substituted;

W is C₂-C₆ straight chain alkyl, substituted C₁-C₆ straight chain alkyl,OCH₃, C₂-C₆ alkoxy, alkylthioalkyl, substituted alkylthioalkyl, C₃-C₈cycloalkyl, substituted C₃-C₈ cycloalkyl, C₅-C₈ aryl, substituted aryl,phenyl, substituted phenyl, CR₁₀═CHR₁₁, alkylthio, benzyl, substitutedbenzyl, heterocyclyl, substituted heterocyclyl, phenoxy, aryloxy,substituted aryloxy, OCR₁₂═CHR₁₃, benzyloxy, heteroaryloxy, substitutedheteroaryloxy, amine, substituted amine, arylamine, substitutedarylamine, phenylamine, substituted phenylamine, CH₃, CF₃, C₃-C₆branched alkyl, C₅-C₈ cycloalkenyl, C₂-C₆ alkynyl, alkylamine,dialkylamine, heteroaryl, CH₂-heterocyclyl, CH₂-substitutedheterocyclyl, OCF₃, alkenoxy, CH₂OR₁₆, thioalkyl, arylthio, thioaryl,alkylthioaryl or alkylcarboxy, phenyl sulfonylamide, or substituted arylsulfonylamide, chlorophenylacetyl;

Z is CH₃, CF₃, C₂-C₆ straight chain alkyl, heteroaryl, substitutedheteroaryl, phenyl, substituted phenyl, C₅-C₈ aryl, substituted C₅-C₈aryl, C₃-C₆ branched alkyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₂-C₆alkynyl, amine, alkylamine, dialkylamine, arylamine, benzyl,heteroaryloxy, heterocyclyl, CH₂-heterocycle, OCH₃, OCF₃, C₂-C₆ alkoxy,alkenoxy, phenoxy, aryloxy or benzyloxy;

R₉ is H, CH₃, C₂-C₆ straight chain alkyl, or C₃-C₆ branched alkyl;

R₁₀, R₁₁, R₁₂, and R₁₃ are each, independently, H, phenyl, C₅-C₈ aryl,CH₃, CF₃, C₂-C₆ straight chain alkyl, C₃-C₈ cycloalkyl, heteroaryl, orheterocyclyl;

R₁₄ and R₁₅ are each, independently H, C₂-C₆ straight alkyl, C₃-C₆branched alkyl, C₃-C₈ cycloalkyl, allyl, C₂-C₆ straight alkenyl,branched alkenyl, C₅-C₈ cycloalkenyl, phenyl, C₅-C₈ aryl, benzyl,CH₂C(OCH₃)₂, heteroaryl, or heterocyclyl; and,

R₁₆ is C₃-C₆ branched alkyl, C₅-C₈ aryl, substituted C₅-C₈ aryl,heteroaryl, phenyl, substituted phenyl, CH₂-aryl, benzyl, H, CH₃, CF₃,C₂-C₆ straight chain alkyl, C₃-C₈ cycloalkyl, heterocyclyl, orCH₂-heteroaryl.

J₂ and J₃ are each, independently, H, F, Cl, Br, I, CR₁₇═CHR₁₈, CF₃,CH₃, C₂-C₆ straight chain alkyl, substituted C₁-C₆ straight chain alkyl,C₃-C₆ branched alkyl, CH₂OR₂₁, phenyl, C₅-C₈ aryl, substituted C₅-C₈aryl, C₃-C₈ cycloalkyl, substituted C₃-C₈ cycloalkyl, CH₂-heterocycle,C₅-C₈ cycloalkenyl, aryloxy, substituted aryloxy, heteroaryl,substituted heteroaryl, heterocyclyl, substituted heterocyclyl, benzyl,alkylamine, substituted alkylamine, benzylamine, OH, CH₃, CF₃,OCR₁₉═CHR₂₀, C₂-C₆ alkynyl, amine, dialkylamine, arylamine, amide,carbamoyl, aminesulfoxide, sulfamide, sulfamoyl, sulfonic acid,heteroaryloxy, OCH₃, OCF₃, C₂-C₆ alkoxy, alkenoxy, phenyloxy, benzyloxy,alkoxycarbonyl, carboxyacid, carboxyalkoxy, carbonylalkyl, thio,alkylthio, thioalkyl, arylthio, thioaryl, alkylthioaryl, or

when J₂=J₃, J₂ is not OH, NH₂, SH, or NO₂; J₂ and J₃ can form a 4, 5; 6,7, 8 membered spiro ring containing 0, 1, or 2 heteroatoms such as O, N,S;

R₁₇, R₁₈, R₁₉, and R₂₀ are each, independently, H, phenyl, C₅-C₈ aryl,CH₃, CF₃, C₂-C₆ straight chain alkyl, C₃-C₈ cycloalkyl, heteroaryl, orheterocyclyl;

R₂₁ is H, C₂-C₆ straight alkyl, C₃-C₆ branched alkyl, C₃-C₈ cycloalkyl,allyl, C₂-C₆ straight alkenyl, branched alkenyl, C₅-C₈ cycloalkenyl,phenyl, C₅-C₈ aryl, benzyl, CH₂C(OCH₃)₂, heteroaryl, or heterocyclyl.

In one embodiment, X═N-J₁, the compound of Formula I has the structureof Formula Ia:

In another embodiment,

the compound of Formula I has the structure of Formula Ib:

In another embodiment, X═O or S, the compound of Formula I has thestructure of Formula Ic or Ib:

In one embodiment, p is 0 and q is 1 and the compound of Formula I hasthe structure of Formula A:

In another embodiment, p is 2 and q is 2 and the compound of Formula Ihas the structure of Formula B:

In another embodiment, p is 2 and q is 3 and the compound of Formula Ihas the structure of Formula C:

In another embodiment, p is 1 and q is 1 and the compound of Formula Ihas the structure of Formula D:

In another embodiment, p is 1 and q is 2 and the compound of Formula Ihas the structure of Formula E:

In another embodiment, p is 2 and q is 1 and the compound of Formula Ihas the structure of Formula F:

Compounds of Formula Ia include those in which R₁, R₂, R₃, and R₄ areeach, independently, H, OH, F, Cl, Br, I, CH₃, CF₃, OCH₃, C₂-C₆, alkoxy,C₂-C₆ straight chain allyl, substituted C₂-C₆ straight chain alkyl,phenyl, C₅-C₈ aryl, NO₂, CN, C(O)NHR₁₄ or NHC(O)R₁₅. For example, R₁,R₂, R₃, and R₄ are each, independently, H, OH, F, Cl, Br, I, CH₃, CF₃,OCH₃, C₂-C₆ alkoxy. In another embodiment, R₁, R₂, R₃, and R₄ are each,independently, H or OCH₃. For example, R₁, R₂ and R₄ are each H and R₃is OCH₃.

Compounds of Formula Ia include those in which J₁ is—(CR₅R₆)_(n)—(CR₇R₈)_(m)—Y. For example, n=1 and m=0. In anotherembodiment, n=1 and m=1. In another embodiment, n=0 and m=0. In anotherembodiment, n=1 and m=2. In another embodiment, n=5 and m=5.

Compounds of Formula Ia include those in which R₅ and R₆ are each,independently, H or CH₃. For example, R₅ and R₆ are each H.

Compounds of Formula Ia include those in which R₇ and R₈ are each,independently, H, F, Cl, Br, I, OH, CH₃, C₂-C₆ straight chain alkyl,CF₃, C₃-C₆ branched alkyl, C₃-C₈ cycloalkyl, or C₂-C₆ alkoxy. Forexample, R₇ and R₈ are each, independently, H or OH.

Compounds of Formula Ia include those in which R₅ and R₆ are each H andR₇ and R₈ are each, independently, H or OH.

Compounds of Formula Ia include those in which Y is CH₂OR₁₆, phenyl,substituted C₅-C₈ aryl or benzyl. In one embodiment, Y is CH₂OR₁₆. Forexample, Y is substituted or unsubstituted C₅-C₈ aryl. In oneembodiment, the substituted C₅-C₈ aryl is substituted with from 1 to 5substituents each of which is independently CN, Cl or F. For example,R₁₆ is substituted or unsubstituted C₅-C₈ aryl. In another embodiment,the substituted C₅-C₈ aryl is substituted with from 1 to 5 substitutentseach of which is independently C₃-C₆ branched alkyl, Cl, or F.

Compounds of Formula Ia include those in which J₁ is —S(O)_(o)-Z. Forexample, o=1 or o=2. In one embodiment, Z is CH₃, CF₃, C₂-C₆ straightchain alkyl, heteroaryl, substituted heteroaryl, phenyl, substitutedphenyl, C₅-C₈ aryl, or substituted C₅-C₈ aryl.

Compounds of Formula Ia include those in which J₁ is

For example, t=1 or t=2. In one embodiment, W is substituted aryl,phenyl, phenoxy, aryloxy and substituted aryloxy. In another embodiment,the aryl and aryloxy is substituted with from 1 to 5 substituents eachof which is independently CF₃ or F. In another embodiment, t=2 and W isC₂-C₆ alkoxy.

Additional compounds of Formula Ia include those in which R₉ is H; R₁₀and R₁₁ are both H; R₁₂ and R₁₃ are both H; R₁₆ is C₃-C₆ branched alkyl,C₅-C₈ aryl, substituted C₅-C₈ aryl, heteroaryl, phenyl, substitutedphenyl, CH₂-aryl, or benzyl. In one embodiment, R₁₂ is H and R₁₃ isphenyl.

Some representative compounds of Formula I are shown as follows:

-   1′-(3-chlorobenzoyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 55);-   1′-(3,4-dichlorobenzoyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 53);-   4-[(5,6-dioxo-5,6-dihydro-1H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-yl)methyl]benzonitrile    (Compound 123);-   1′-(2-phenylethyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 155);-   1′-(4-fluorobenzyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 125);-   1′-[3-(4-tert-butylphenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 157);-   1′-(2-hydroxy-3-phenylpropyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 163);-   3-(trifluoromethyl)phenyl    5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylate    (Compound 96);-   4-fluorophenyl    5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylate    (Compound 97);-   1′-(2-chloro-6-fluorobenzyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 129);-   1′-(3-chloro-4-fluorobenzyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 142);-   1′-(3-phenoxypropyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 144);-   1′-[2-(4-chlorophenoxy)ethyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 145);-   1′-[(2S)-3-(4-fluorophenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 180);-   1′-[(2S    )-3-(4-tert-butylphenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 184);-   1′-[(2R)-3-(4-tert-butylphenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 185);-   1′-[(2R)-3-(4-fluorophenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 181);-   1′-[(2S)-3-(4-chlorophenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 182);-   1′-[(2R)-3-(4-chlorophenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 183);-   1′-[(2R)-2-hydroxy-3-phenylpropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 186);-   1′-[(2S)-2-hydroxy-3-phenylpropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 187);-   1′-[(2S)-2-hydroxy-3-(2-methylphenoxy)propyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 200);-   1′-isopropyl    spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 152);-   1′-[(2S)-3-(4-ethylphenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 207);-   1′-[(2R)-3-(4-ethylphenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 228);-   1′-[(2R)-2-hydroxy-3-(2-methylphenoxy)propyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione    (Compound 224).

Representative compounds of the present invention are also shown in theExamples.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. In case of a conflict interminology, the present specification controls. The following termsgenerally have the following meanings.

1.1. Definitions

As used herein, the term “alkyl” includes saturated aliphatic groups,including straight-chain alkyl groups (e.g., methyl, ethyl, propyl,butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl), branched-chain alkylgroups (e.g., isopropyl, tert-butyl, isobutyl). “Alkyl” further includesalkyl groups that have oxygen, nitrogen, or sulfur atoms replacing oneor more hydrocarbon backbone carbon atoms. In certain embodiments, astraight chain or branched alkyl has six or fewer carbon atoms in itsbackbone (e.g., C₁-C₆ for straight chain, C₃-C₆ for branched chain), andmore preferably four or fewer.

The term “alkyl” also includes both “unsubstituted” and “substitutedalkyls”, the latter of which refers to alkyl moieties havingsubstituents replacing a hydrogen on one or more carbon of thehydrocarbon backbone. Such substitutents can include, for example,alkyl, alkenyl, alkynyl, hydroxyl, alkylcarbonyl, arylcarbonyl,alkoxycarbonyl, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,carboxyacid, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl,cyano, amino (including alkylamino, dialkylamino, arylamino,diarylamino, and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino,imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,alkylsulfinyl, sulfonato, sulfamoyl (S(O)₂NH₂), aminesulfoxide (NHS(O)or S(O)NH), sulfonamide (NHS(O)₂ or S(O)₂NH), nitro, —CF₃, halogen,cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromaticmoiety. An “alkylaryl” or aralkyl moiety is an alkyl moiety substitutedwith an aryl (e.g., methylphenyl (benzyl)). “Alkyl” also includes theside chains of natural and unnatural amino acids.

Aryl includes groups with aromaticity, including 5- and 6-membered“unconjugated”, or single-ring aromatic groups that may include from oneto four heteroatoms, as well as “conjugated”, or multicyclic systemswith at least one aromatic ring. Examples of aryl groups include phenyl,pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole,tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine,and pyrimidine, and the like. Furthermore, the term aryl includesmulticyclic groups, e.g., tricyclic, bicyclic, e.g., naphthalene,benzoxazole, benzodioxazole, benzothizole, benzoimidazole,benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline,napthridine, indole, benzofuran, purine, benzofuran, deazapureine, orindolizine. Those aryl groups having heteroatoms in the ring structuremay also be referred to as “aryl heterocycles”, “heterocycles”,“heterocyclyls”, “heteroaryls” or “heteroaromatics” e.g., pyridine,pyrazole, pyrimidine, furan, isoxazole, imidazole[2,1,b]thiazole,triazole, pyrazine, benzothiophene, imidazole, or thiophene.

The aromatic ring can be substituted at one or more ring positions withsuch substituents as described above, as for example, halogen, hydroxyl,alkyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, carboxyacid, alkylcarbonyl,alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl,alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl,alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, cyano,amino (including alkylamino, dialkylamino, arylamino, diarylamino, andalkylarylamino), acylamino (including alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl,alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Arylgroups can also be fused or bridged with alicyclic or heterocyclicrings, which are not aromatic so as to form a multicyclic system (e.g.,tetralin, methylenedioxyphenyl).

“Alkenyl” includes unsaturated aliphatic groups analogous in length andpossible substitution to the alkyls described above, but that contain atleast one double bond. For example, the term “alkenyl” includesstraight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl,pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), branched-chainalkenyl groups, cycloalkenyl (e.g., alicyclic) groups (e.g.,cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,cyclooctenyl), alkyl or alkenyl substituted cycloalkenyl groups, andcycloalkyl or cycloalkenyl substituted alkenyl groups. The term“alkenyl” further includes alkenyl groups, which include oxygen,nitrogen, or sulfur replacing one or more hydrocarbon backbone carbons.In certain embodiments, a straight chain or branched chain alkenyl grouphas six or fewer carbon atoms in its backbone (e.g., C₂-C₆ for straightchain, C₃-C₆ for branched chain.) Likewise, cycloalkenyl groups may havefrom three to eight carbon atoms in their ring structure, and morepreferably have five or six carbons in the ring structure. The term“C₂-C₆” includes alkenyl groups containing two to six carbon atoms.

The term “alkenyl” also includes both “unsubstituted alkenyls” and“substituted alkenyls”, the latter of which refers to alkenyl moietieshaving substituents replacing a hydrogen on one or more hydrocarbonbackbone carbon atoms. Such substituents can include, for example, alkylgroups, alkenyl groups, alkynyl groups, halogens, hydroxyl,alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, carboxyacid, alkylcarbonyl,arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, cyano, amino(including alkylamino, dialkylamino, arylamino, diarylamino, andalkylarylamino), acylamino (including alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl,alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,phenyl, heterocyclyl, alkylaryl, or an aromatic or heteroaromaticmoiety.

“Alkynyl” includes unsaturated aliphatic groups analogous in length andpossible substitution to the alkyls described above, but which containat least one triple bond. For example “alkynyl” includes straight chainalkynyl groups (e.g., ethyl, propynyl, butynyl, pentynyl, hexynyl,heptynyl, octynyl, nonynyl, decynyl), branched chain alkynyl groups, andcycloalkyl or cycloalkenyl substituted alkynyl groups. The term“alkynyl” further includes alkynyl groups having oxygen, nitrogen,sulfur or phosphorous atoms replacing one or more hydrocarbon backbonecarbons. In certain embodiments, a straight chain or branched chainalkynyl group has six or fewer carbon atoms in its backbone (e.g., C₂-C₆for straight chain, C₃-C₆ for branched chain). The term “C₂-C₆” includesalkynyl groups containing two to six carbon atoms.

The term “alkynyl” also includes both “unsubstituted alkynyls” and“substituted alkynyls”, the latter of which refers to alkynyl moietieshaving substitutents replacing a hydrogen on one or more hydrocarbonbackbone carbon atoms. Such substitutents can include, for example,alkyl groups, alkenyl groups, alkynyl groups, halogens, hydroxyl,alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, carboxyacid, alkylcarbonyl,arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, cyano, amino(including alkylamino, dialkylamino, arylamino, diarylamino, andalkylarylamino), acylamino (including alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl,alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

Unless the number of carbons is otherwise specified, “lower alkyl”includes an alkyl group, as defined above, but having from one to ten,more preferably from one to six, carbon atoms in its backbone structure.“Lower alkenyl” and “lower alkynyl” have chain lengths of, for example,2-5 carbon atoms.

As used herein, “amine” or “amino” includes compounds where a nitrogenatom is covalently bonded to at least one carbon or heteroatom.“Alkylamino” includes groups of compounds wherein nitrogen is bound toat least one additional alkyl group. Examples of alkylamino groupsinclude benzylamino, methylamino, ethylamino, and phenethylamino.“Dialkylamino” includes groups wherein the nitrogen atom is bound to atleast two additional alkyl groups. Examples of dialkylamino groupsinclude dimethylamino and diethylamino. “Arylamino” and “diarylamino”include groups wherein the nitrogen is bound to at least one or two arylgroups, respectively. “Alkylarylamino,” “alkylaminoaryl” or“arylaminoalkyl” refers to an amino group which is bound to at least onealkyl group and at least one aryl group. “Alkaminoalkyl” refers to analkyl, alkenyl, or alkynyl group bound to a nitrogen atom which is alsobound to an alkyl group.

The term “amide” or “aminocarboxy” includes compounds or moieties thatcontain a nitrogen atom that is bound to the carbon of a carbonyl or athiocarbonyl group. The term includes “alkaminocarboxy” groups thatinclude alkyl, alkenyl, or alkynyl groups bound to an amino group boundto a carboxy group. It includes arylaminocarboxy groups that includearyl or heteroaryl moieties bound to an amino group that is bound to thecarbon of a carbonyl or thiocarbonyl group. The terms“alkylaminocarboxy,” “alkenylaminocarboxy,” “alkynylaminocarboxy,” and“arylaminocarboxy” include moieties wherein alkyl, alkenyl, alkynyl andaryl moieties, respectively, are bound to a nitrogen atom which is inturn bound to the carbon of a carbonyl group. Amides can be substitutedwith substitutents such as straight chain alkyl, branched alkyl,cycloalkyl, aryl, heteroaryl, or heterocycle. Substitutents on amidegroups may be further substituted.

“Acyl” includes compounds and moieties that contain the acyl radical(CH₃CO—) or a carbonyl group. “Substituted acyl” includes acyl groupswhere one or more of the hydrogen atoms are replaced by for example,alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,carboxyacid, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl,cyano, amino (including alkylamino, dialkylamino, arylamino,diarylamino, and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety.

“Acylamino” includes moieties wherein an acyl moiety is bonded to anamino group. For example, the term includes alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido groups.

The term “alkoxy” or “alkoxyl” includes substituted and unsubstitutedalkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom.Examples of alkoxy groups (or alkoxyl radicals) include methoxy, ethoxy,isopropyloxy, propoxy, butoxy, and pentoxy groups. Examples ofsubstituted alkoxy groups include halogenated alkoxy groups. The alkoxygroups can be substituted with groups such as alkenyl, alkynyl, halogen,hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, carboxyacid, alkylcarbonyl,arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, cyano, amino(including alkylamino, dialkylamino, arylamino, diarylamino, andalkylarylamino), acylamino (including alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl,alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties.Examples of halogen substituted alkoxy groups include, but are notlimited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy,chloromethoxy, dichloromethoxy, and trichloromethoxy.

The term “cycloalkyl” includes saturated acyclic groups (e.g.,cyclopropyl, cyclopentyl, cyclohexyl, cyclohexyl, cycloheptyl,cyclooctyl). Preferred cycloalkyls have from three to eight carbon atomsin their ring structure, and more preferably have five or six carbonatoms in the ring structure. Cycloalkyls includes both “unsubstitutedcycloalkyls” and “substituted cycloalkyls”, the latter of which refersto replacing a hydrogen on one or more of the carbons in the ringstructure. Such substituents can include, for example, alkyl, alkenyl,alkynyl, halogen; hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, carboxyacid,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl alkylthiocarbonyl, alkoxyl,cyano, amino (including alkylamino, dialkylamino, arylamino,diarylamino, and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety.

The terms “heterocyclyl” or “heterocyclic group” include closed ringstructures, e.g. 3- to 10-, or 4- to 7-membered rings, which include oneor more heteroatoms. “Heteroatom” includes atoms of any element otherthan carbon or hydrogen. Examples of heteroatoms include nitrogen,oxygen, or sulfur.

Heterocyclyl groups can be saturated or unsaturated and includepyrrolidine, pyrazine, pyrimidine, oxolane, 1,3-dioxolane, thiolane,tetrahydrofuran, tetrahydropyran, piperidine, piperazine, pyrrolidine,morpholine, lactones, lactams such as azetidinones and pyrrolidinones,sultams, and sultones. Heterocyclic groups such as pyrrole and furan canhave aromatic character. They include fused ring structures such asquinoline and isoquinoline. Other examples of heterocyclic groupsinclude pyridine and purine. The heterocyclic ring can be substituted atone or more positions with such substituents as described above, as forexample, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, carboxyacid,alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl,alkoxyl, cyano, amino (including alkyl amino, dialkylamino, arylamino,diarylamino, and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,heterocyclyl, or an aromatic or heteroaromatic moiety. Heterocyclicgroups can also be substituted at one or more constituent atoms with,for example, a lower alkyl, a lower alkenyl, a lower alkoxy, a loweralkylthio, a lower alkylamino, a lower alkylcarboxyl, a nitro, ahydroxyl, —CF₃, or —CN, or the like.

The term “thioalkyl” includes compounds or moieties which contain analkyl group connected with a sulfur atom. The thioalkyl groups can besubstituted with groups such as alkyl, alkenyl, alkynyl, halogen,hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, carboxyacid, alkylcarbonyl,arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, cyano, amino(including alkylamino, dialkylamino, arylamino, diarylamino, andalkylarylamino), acylamino (including alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl,alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties.

The term “carbonyl” or “carboxy” includes compounds and moieties whichcontain a carbon connected with a double bond to an oxygen atom.Examples of moieties containing a carbonyl include, but are not limitedto, aldehydes, ketones, carboxylic acids, amides, esters, anhydrides,etc.

The term “thiocarbonyl” or “thiocarboxy” includes compounds and moietieswhich contain a carbon connected with a double bond to a sulfur atom.

The ter “hydroxy” or “hydroxyl” includes groups with an —OH or —O⁻.

The term “halogen” includes fluorine, bromine, chlorine, iodine, etc.The term “perhalogenated” generally refers to a moiety wherein allhydrogens are replaced by halogen atoms.

The term “C1-C6” includes one to six carbon atoms (C1, C2, C3, C4, C5 orC6). The term “C2-C6” includes two to six carbon atoms (C2, C3, C4, C5or C6). The term “C3-C6” includes three to six carbon atoms (C3, C4, C5or C6). The term “C3-C8” includes two to eight carbon atoms (C3, C4, C5,C6, C7 or C8). The term “C5-C8” includes five to eight carbon atoms (C5,C6, C7 or C8).

It should be noted that any heteroatom or carbon atom with unsatisfiedvalences is assumed to have the hydrogen atom to satisfy the valences.

The compounds described herein may have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.Many geometric isomers of olefins, C═N double bonds, and the like canalso be present in the compounds described herein, and all such stableisomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. All chiral, diastereomeric, racemic, and geometricisomeric forms of a stricture are intended, unless the specificstereochemistry or isomeric form is specifically indicated. Alltautomers of shown or described compounds are also considered to be partof the present invention.

It is to be understood accordingly that the isomers arising from suchasymmetry (e.g., all enantiomers and diastereomers) are included withinthe scope of the invention, unless indicated otherwise. Such isomers canbe obtained in substantially pure form by classical separationtechniques and by stereochemically controlled synthesis. Furthermore,the structures and other compounds and moieties discussed in thisapplication also include all tautomers thereof. Alkenes can includeeither the E- or Z-geometry, where appropriate.

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced. Keto substituents are not present on aromatic moieties. Ringdouble bonds, as used herein, are double bonds that are formed betweentwo adjacent ring atoms (e.g. C═C, C═N, or N═N). “Stable compound” and“stable structure” are meant to indicate a compound that is sufficientlyrobust to survive isolation to a useful degree of purity from a reactionmixture, and formulation into an efficacious therapeutic agent.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom in thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substitutents and/or variables arepermissible, but only if such combinations result in stable compounds.

In the specification, the singular forms also include the plural, unlessthe context clearly dictates otherwise.

2. The Synthesis of Lapachone Compounds

The present invention also provides methods for the synthesis of thecompounds of Formula I. In one embodiment, the present inventionprovides a method for the synthesis of compounds according to thefollowing schemes, and the protocols shown in the Examples.

Throughout the description, where compositions are described as having,including, or comprising specific components, it is contemplated thatcompositions also consist essentially of, or consist of, the recitedcomponents. Similarly, where methods or processes are described ashaving, including, or comprising specific process steps, the processesalso consist essentially of, or consist of, the recited processingsteps. Further, it should be understood that the order of steps or orderfor performing certain actions is immaterial so long as the inventionremains operable. Moreover, two or more steps or actions can beconducted simultaneously.

The synthetic processes of the invention can tolerate a wide variety offunctional groups, therefore various substituted starting materials canbe used. The processes generally provide the desired final compound ator near the end of the overall process, although it may be desirable incertain instances to further convert the compound to a pharmaceuticallyacceptable salt, ester, or prodrug thereof.

Compounds of the invention can be prepared in a variety of ways, some ofwhich are known in the art. In general, the compounds of the presentinvention can be prepared from commercially available startingmaterials, compounds known in the literature, or from readily-preparedintermediates, by employing standard synthetic methods and proceduresknown to those skilled in the art, or which will be apparent to theskilled artisan in light of the teachings herein. Standard syntheticmethods and procedures for the preparation of organic molecules andfunctional group transformations and manipulations can be obtained fromthe relevant scientific literature or from standard textbooks in thefield. Although not limited to any one or several sources, classic textssuch as Smith, M. B.; March, J. March's Advanced Organic Chemistry:Reactions, Mechanisms, and Structure, 5^(th) ed.; John Wiley & Sons: NewYork, 2001; and Greene, T. W.; Wuts, P. G. M. Protective Groups inOrganic Synthesis, 3^(rd).; John Wiley & Sons: New York, 1999,incorporated by reference herein, are useful and recognized referencetextbooks of organic synthesis known to those in the art. The followingdescriptions of synthetic methods are designed to illustrate, but notlimit, general procedures for the preparation of compounds of theinvention.

The compounds of this invention with general formula (I) may be preparedaccording to the following schemes from commercially available startingmaterials or starting materials, which can be prepared using literatureprocedures. These schemes show the preparation of representativecompounds of this invention.

The compounds of the present invention can be prepared from the reactionof spiro-1,2-quinone (Ia) and appropriate intermediate/commercialreagents. (Scheme 9)

Compounds of formula (Ia) can be conveniently prepared by a variety ofmethods familiar to those skilled in the art. One common route isillustrated in Scheme 1. Epoxide compounds such as formula (IV) may beconveniently prepared from ketones of formula (III) where J₁ is aprotecting group such as tert-butyl carbamate (t-BOC).Trimethylsulfoxonium ylide is prepared by treating trimethylsulfoxoniumiodide with bases such as sodium hydride in a polar solvent such asanhydrous dimethylsulfoxide. Other bases such as potassium t-butoxidemay also be used instead of sodium hydride. The trimethylsulfoxoniumylide is treated with ketone of formula (III) at 0° C. initially and thereaction warmed to room temperature for 4-24 hours to provide epoxide(IV). (Hale, J. et al, Bioorganic & Medicinal Chemistry Letters, 2002,12(20), 297; Jambulingam M et al, Asian Journal of Chemistry, 2004,16(3-4), 1261) Many ketones are commercially available or readilyprepared by methods described in the literature and known to thoseskilled in art. Alternatively, the epoxide (IV) can also be convenientlyprepared from alkenes (V) by treatment with peroxy acids suchm-chloroperoxybenzoic acid. Many alkenes are commercially available orreadily prepared from ketones (III) by methods described in theliterature [Abell A. et al, Organophosphorus Reagents, 2004, 99;Lawrence N. et al, Preparation of Alkenes, 1996, 19; Edmonds M. et al,Modern Carbonyl Olefination 2004, 1] and known to those skilled in art.

The epoxides (IV) are used to prepare thioalcohol compounds of formula(VI). These can be conveniently prepared by a variety of methodsfamiliar to those skilled in the art. The epoxide (IV) is treated with apretreated mixture of sodium sulfide and acids such as p-toluenesulfonic acid in polar protic solvent such as methanol for 0.5-4 hoursat a temperature of 0-25° C. to provide the thioalcohol (VI). Anothercommon route to prepare thialcohols (VI) is by treating epoxide (IV)with triphenylsilane thiol, tertiary amine bases such as triethyl amineand in polar protic solvent such as methanol for 0.5-4 hours at ambienttemperatures (Brittain J. et al, Tetrahedron Letters, 1993, 34(21),3363).

The thioalcohols (VI) are used to prepare 1,2-quinone alcohol compoundsof formula (VIII). These can be conveniently prepared by methodsfamiliar to those skilled in the alt. The thioalcohol (VI) is treatedwith 1,2-quinones (VII), bases such as potassium carbonate and solventssuch as tetrahydrofuran for 0.5-4 hours at ambient temperatures toprovide the 1,2-quinone alcohols with formula (VIII). Alternativelybases such as triethylamine, sodium carbonate, cesium carbonate andsolvents such as acetonitrile dichloromethane can also be utilized.

1,2-Quinone alcohols (VIII) are used to prepare spiro-1,2-quinonecompounds with formula (II). These can be conveniently prepared bymethods familiar to those skilled in the art. 1,2-Quinone alcohols withformula (VIII) are treated with acid such as trifluoroacetic acid andsolvents such as dichloromethane in open air at ambient temperature for24-96 hours. Alternatively acids such as p-toluenesulfonic acid,sulfuric acid can also be used and air or oxygen can also be bubbledthrough the reaction.

Compounds of formula (VII) can be conveniently prepared by a variety ofmethods familiar to those skilled in the art. One common route isillustrated in Scheme 2. Naphthols (IX-X) are treated with a solution ofphenylselenic anhydride in solvent such as tetrahydrofuran for 15-30minutes at a temperature of 60-80° C. to provide the 1,2-quinones withformula (VII). Many naphthols are commercially available or readilyprepared by methods described in the literature and known to thoseskilled in art. (Cordero-Vargas, A. et al, Org. Biomol. Chem. 2004, 2,3018; Adcock, W. et al, J. Am. Chem. Soc. 1967, 89(2), 386; Gareau, Y.et al, WO 99/47497)

Compounds of formula (Ia) where J₁ is a protecting group such astert-butyl carbamate (t-BOC) can be conveniently prepared by methodsfamiliar to those skilled in the art. One common route is illustrated inScheme 3. Thioalcohol (VI) is treated with 1,2-quinones (VII), basessuch as potassium carbonate and solvents such as tetrahydrofuran for0.5-4 hours at ambient temperatures to provide the 1,2-quinone alcohols(VIII). The resulting crude 1,2-quinone alcohols (VIII) is treated withacid such as trifluoroacetic acid and solvents such as dichloromethanein open air at ambient temperature for 24-96 hours to provide thespiro-1,2-quinone compounds with formula (II). The resulting crudespiro-1,2-quinone compounds (II) are treated with di-tert-butyldicarbonate in bases such as aqueous sodium bicarbonate, solvent such asdichloromethane for 0.25-4 hours at ambient temperature to provide thet-butoxycarbamate (t-BOC) protected spiro-1,2-quinones compounds withformula (Ia).

Compounds of formula (II) can also be prepared as shown in Scheme 4.Thioalcohol (VI) where J₁ is a protecting group such as tert-butylcarbamate (t-BOC) is treated with 1,2-quinones (VII), bases such aspotassium carbonate and solvents such as tetrahydrofuran for 0.5-4 hoursat ambient temperatures to provide the 1,2-quinone alcohols (VIII). Theresulting crude 1,2-quinone alcohols (VIII) are treated with acid suchas trifluoroacetic acid and solvents such as dichloromethane in open airat ambient temperature for 24-96 hours to provide the spiro-1,2-quinonecompounds with formula (II).

Another common route for the preparation of compounds of formula (VIII)where J₁ is a protecting group such as tert-butyl carbamate (t-BOC) isshown in Scheme 5. Thioalcohol (VI) is treated with 4-chloro-1,2-quinone(XI), bases such as potassium carbonate and solvents such astetrahydrofuran for 0.5-4 hours at ambient temperatures to provide the1,2-quinone alcohols with formula (VIII). Alternatively other4-halo-1,2-quinones such as 4-bromo-1,2-quinone, bases such astriethylamine, sodium carbonate, cesium carbonate and solvents such asacetonitrile, dichloromethane can also be utilized. Many4-halo-1,2-quinones are readily prepared by methods described in theliterature and known to those skilled in art. (Paquet, J. et al,Canadian Journal of Chemistry, 1989, 67(8), 1354; Perumal, T. et al,1980, 11, 943; Krohn K. et al, Synthesis, 1990, 12, 1141).

Another common route for the preparation of compounds of formula (II) isshown in Scheme 6. Thioalcohol (VI) where J₁ is a protecting group suchas t-butyl carbamate (t-BOC) is treated with 4-chloro-1,2-quinone (XI),tertiary amine bases such as triethylamine and solvents such asdichloromethane for 0.5-4 hours at ambient temperatures. To the reactionis added acids such as trifluoroacetic acid to provide thespiro-1,2-quinone (II). This example illustrates how spiro-1,2-quinone(II) can be conveniently prepared without isolating 1,2-quinone alcohols(VIII).

Another common route for the preparation of compounds of formula (Ia andII) where J₁ is a protecting group such as tert-butyl carbamate (t-BOC)is illustrated in Scheme 7. 1,2-Quinone alcohols (VIII) are treated with1-3 equivalents of acids such as trifluoroacetic acid, oxidants such assodium iodate and solvents such as dichloromethane at ambienttemperature for 24-96 hours to provide the spiro-1,2-quinones compoundswith formula (Ia and II). Alternatively acids such as p-toluenesulfonicacid can also be used.

Compounds of formula (II) where can also be prepared as shown in Scheme8. Spiro-1,2-quinones (II) can be prepared by treatingspiro-1,2-quinones (Ia) where J₁ is a protecting group such astert-butyl carbamate (t-BOC) with acids such as trifluoroacetic acid insolvents such as dichloromethane or solution of hydrogen chloride gas insolvents such as ethyl acetate, 1,2-dioxane, diethyl ether at ambienttemperature for 1-24 hours. The product spiro-1,2-quinones (II) can beisolated as free base, hydrochloride or trifluoroacetic acid salt. Toobtain the free base an aqueous workup with sodium bicarbonate iscarried out on either acid salt. The above condition also describes amethod to remove the protecting group tert-butyl carbamate (t-BOC) groupfrom amines.

Scheme 9 illustrates a variety of chemical transformation ofspiro-1,2-quinone (II) to provide compounds (XII-XXI). The followingmethods are provided by way of exemplification. Alternative methods maybe employed and are described in reference text's such as ComprehensiveOrganic Transformations, Richard C. Larock, Second Edition, Wiley-VCH,1999; Protective Groups in Organic Synthesis, Third Edition, Theodora W.Greene and Peter M. Wuts, Wiley Interscience, 1999; The Practice ofPeptide Synthesis, M. Bodanszky and A. Bodanzsky, Springer-Verlag, 1984.

The spiro-1,2-quinone amide (XII) can be conveniently prepared bytreating spiro-1,2-quinone (II) with acid chlorides such asm-trifluoromethylbenzoyl chloride in presence of tertiary anine basessuch as triethylamine, diisopropylethyl amine and solvents such asdichloromethane at ambient temperature for 1-12 hours. Many acidchlorides are commercially available or readily prepared by methodsdescribed in the literature and known to those skilled in art.

Alternatively spiro-1,2-quinone amide (XII) can be conveniently preparedby treating spiro-1,2-quinone (II) with the corresponding carboxylicacid in presence of amide coupling agents such as HBTU(O-(benzotriazo-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate),tertiary amine bases such as dimethylaminopyridine and solvents such asdimethylformamide at ambient temperature for 4-24 hours. Alternativelyamide coupling agents such as DCC (dicylcohexycarbodiimide), BOP((benzotriazo-1-yloxy)tris(dimethylamino) phosphoniumhexafluorophosphate, EDCI.HCl (1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride), DMC(2-chloro-1,3-dimethylimidazolinium chloride) and tertiary amines basessuch as triethylamine, diisopropylethyl amine can also be used. Manycarboxylic acids are commercially available or readily prepared bymethods described in the literature and known to those skilled in art.

Spiro-1,2-quinone sulfonamide (XIII) can be conveniently prepared bytreating spiro-1,2-quinone (II) with sulfonyl chlorides such asmethanesulfonyl chloride in presence of tertiary amine bases such astriethylamine and solvents such as dichloromethane at ambienttemperature for 1-12 hours. Alternatively tertiary amines bases such asdiisopropylethyl amine can also be used. Many sulfonyl chlorides arecommercially available or readily prepared by methods described in theliterature and known to those skilled in art.

Spiro-1,2-quinone amino alcohol (XIV) can be conveniently prepared bytreating spiro-1,2-quinone (II) with epoxides such as(2S)-2-[(4-t-butyl-phenoxy)methyl]oxathiine in solvents such asacetonitrile, ethanol and with or without lithium perchlorate at 50-100°C. for 1-12 hours. The above conditions can be used with both chiral andracemic epoxide to prepare both chiral and racemic amino alcohols,respectively. Many epoxide both chiral and racemic are commerciallyavailable or readily prepared by methods described in the literature andknown to those skilled in art. (Schaus et. al J. Am. Chem. Soc. 124 (7)2002, 1307-1315; Steffan et. al. Bioorg. Med. Chem. Lett. 2002, 12,2957-2961)

Spiro-1,2-quinone urea (XV) can be conveniently prepared by treatingspiro-1,2-quinone (II) with isocyanates such as phenylisocyanate insolvents such as dichloromethane at ambient temperature for 1-12 hours.Many isocyanates are commercially available or readily prepared bymethods described in the literature and known to those skilled in art.Isocyantes can also be prepared in situ from carboxylic acids by avariety of methods familiar to those skilled in the art. Carboxylicacids are treated with diphenyl phosphoryl azide in solvents such astoluene at reflux for 1-5 hours. The isocyanates are used in situ assolution to react with the spiro-1,2-quinones (II) to preparespiro-1,2-quinone ureas (XV) as described above.

Spiro-1,2-quinone carbamate (XVI) can be conveniently prepared bytreating spiro-1,2-quinone (II) with carbamoyl chlorides such asphenylchlorido carbonate, bases such as triethylamine, diisopropylethylamine, aqueous sodium carbonate in solvents such as ethyl acetate,dichloromethane at ambient temperature for 1-12 hours. Many carbamatesare commercially available or readily prepared by methods described inthe literature and known to those skilled in art. Carbamoyl chloridescan also be prepared in situ from carboxylic acids by a variety ofmethods familiar to those skilled in the art. Carboxylic acids aretreated with oxalyl chloride, triphosgenes in solvents such asdichloromethane at 0° C. to ambient temperature for 1-5 hours. Theresulting carbamoyl are used in situ as solution to react with thespiro-1,2-quinones (II) to prepare spiro-1,2-quinone carbamates withformula (XVI) as described above.

Spiro-1,2-quinone sulfonyl urea (XVII) where X is nitrogen can beconveniently prepared by treating spiro-1,2-quinone (II) with sulfonylisocyanates such as phenylsulfonyl isocyanate (XVIII) in solvents suchas dichloromethane at 0° C. to ambient temperature for 1-12 hours. Manysulfonyl isocyanates are commercially available or readily prepared bymethods described in the literature and known to those skilled in art.

Spiro-1,2-quinone guanidine with formula (XVIII) can be convenientlyprepared by treating spiro-1,2-quinone (II) with pyrazole carboxamidinehydrochloride, tertiary amine bases such as triethylamine,diisopropylethyl amine and in solvents such as dimethylformamide at50-90° C. for 1-12 hours. The crude spiro-1,2-quinone guanidine (XVIII)are titurated with diethyl ether to provide pure spiro-1,2-quinoneguanidine (XVIII) isolated as HCl salts.

Alternatively alkyl substituted spiro-1,2-quinone guanidines can beconveniently prepared by treating spiro-1,2-quinone (II) withbis(tert-butoxycarbonyl)-S-methylisothiourea, mercuric (II) chloride,tertiary amine bases such as triethylamine, diisopropylethyl amine andin solvents such as dimethylformamide at 50-90° C. for 1-12 hours. Theresulting bis(tert-butoxycarbonyl) protected guanidine can be treatedwith benzyl bromide or other alkyl halides in presence of phase transfercatalyst such as tert-butyl ammonium iodide, bases such as potassiumhydroxide in water and organic solvent such as toluene at 40-70° C. for1-8 hours to provide alkyl substituted bis(tert-butoxycarbonyl)protected guanidine. Treatment of the alkyl substitutedbis(tert-butoxycarbonyl) protected guanidine with acids such astrifluoroacetic acid in solvents such as dichloromethane or solution ofhydrogen chloride gas in solvents such as ethyl acetate, 1,2-dioxane,diethyl ether at ambient temperature for 1-24 hours provided alkylsubstituted guanidine as hydrochloride salt. Many alkyl halides such asalkyl chloride, bromide and iodides are commercially available orreadily prepared by methods described in the literature and known tothose skilled in art.

Spiro-1,2-quinone alkyl amines (XIX) can be conveniently prepared bytreating spiro-1,2-quinone (II) with alkyl halides such as2-bromopropane, bases such as potassium carbonate, cesium carbonate,triethylamine, diisopropylethyl amines in solvent such as acetonitrile,dimethylformamide at 70-90° C. for 1-12 hours. Alternatively alkylchloride can be treated with the spiro-1,2-quinone (II) in presence ofsodium iodide (to in situ prepare alkyl iodide) to providespiro-1,2-quinone alkyl amines (XIX). Many alkyl halides arecommercially available or readily prepared by methods described in theliterature and known to those skilled in art.

Spiro-1,2-quinone amine heterocycle (XX) can be conveniently prepared bytreating spiro-1,2-quinone (II) with heterocyclic halides such as2-chloropyrazine, tertiary amine bases such as triethylamine,diisopropylethyl amines in polar aprotic solvent such asdimethylsulfoxide dimethylformamide at 80-110° C. for 1-12 hours. Manyheterocyclic halides are commercially available or readily prepared bymethods described in the literature and known to those skilled in art.

Spiro-1,2-quinone amide acids (XXI) can be conveniently prepared bytreating spiro-1,2-quinone (II) with anhydrides such asdihydrofuran-2,5-dione in solvent such as acetonitrile,dimethylsulfoxide at 70-90° C. for 1-12 hours. Many anhydrides arecommercially available or readily prepared by methods described in theliterature and known to those skilled in art.

As shown in Scheme 10, phenyl spiro-1,2-quinones (XXII) where J₁ is aprotecting group such as tert-butyl carbamate (t-BOC) can beconveniently prepared by treating tert-butoxy carbamate protectedbromo-spiro-1,2-quinone amine (XXII) with boronic acids such as phenylboronic acid Pd(0) catalyst such as Pd(Ph₃P)₄, bases such as sodiumbicarbonate, cesium carbonate in solvent such as ethanol, toluene at70-100° C. for 1-12 hours. Many aromatic boronic acids are commerciallyavailable or readily prepared by methods described in the literature andknown to those skilled in art. (Prieto M. et al, JOC, 2004, 69(20),6812)

As shown in Scheme 11, phenyl amino substituted spiro-1,2-quinones(XXIV) where J₁ is a protecting group such as tert-butyl carbamate(t-BOC) can be conveniently prepared by treating tert-butoxy carbamateprotected bromo-spiro-1,2-quinone amine (XXII) with amines such aspiperidine, Pd(0) catalyst such as bis(tri-tert-butylphosphine)palladium(0), bases such as cesium carbonate, sodiumbicarbonate in solvent such as dioxane at 70-130° C. for 1-12 hours.Many secondary amines are commercially available or readily prepared bymethods described in the literature and known to those skilled in art.(J. Am. Chem. Soc., 2002, 124, 14844)

As shown in Scheme 12, spiro-1,2-quinone amino alcohol esters (XXV) canbe conveniently prepared by treating spiro-1,2-quinone amino alcohols(XIV) with anhydride such as acetic anhydride, tertiary amine base suchas dimethylamino pyridine, triethylamine, diisopropylethylamine insolvent such as dichloromethane at 0° C. to ambient temperatures for1-12 hours. Many anhydrides are commercially available or readilyprepared by methods described in the literature and known to thoseskilled in art.

Alternatively the spiro-1,2-quinone amino alcohol esters with formula(XXVI) can be conveniently prepared by treating spiro-1,2-quinone aminoalcohols (XIV) with carboxylic acids such asN-(tert-butoxycarbonyl)glycine, in presence of ester coupling agentssuch as HBTU (O-(benzotriazo-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate), tertiary amine bases such asdimethylaminopyridine, solvents such as dimethylformamide at ambienttemperatures for 4-24 hours. Many carboxylic acids including protectedamino acids both chiral and racemic are commercially available orreadily prepared by methods described in the literature and known tothose skilled in art.

As shown in Scheme 13, spiro-1,2-quinone acid (XXVIII) can beconveniently prepared by treating spiro-1,2-quinone benzyl ester (XXVII)with Pd (0) on carbon, in an atmosphere of hydrogen and with solventssuch as ethyl acetate at ambient temperatures for 4-24 hours.

The compounds of the present invention having the formula (Ic and Id)where X is oxygen and sulfur can be conveniently prepared as shown inScheme 14. Epoxide compounds (XXX) where X is oxygen and sulfur may beconveniently prepared from ketones (XXIX) where X is oxygen and sulfur.Trimethylsulfoxonium ylide is prepared by treating trimethylsulfoxoniumiodide with bases such as sodium hydride in a polar solvent such asanhydrous dimethylsulfoxide. Other bases such as potassium t-butoxidemay also be used instead of sodium hydride. The trimethylsulfoxoniumylide is treated with ketone (XXIX) at 0° C. initially and the reactionwarmed to room temperature for 4-24 hours to provide epoxide (XXX). Manyketones are commercially available or readily prepared by methodsdescribed in the literature and known to those skilled in art.Alternatively, the epoxide (XXX) where X is oxygen or sulfur substitutedwith phenyl can also be conveniently prepared from alkenes (XXIX) bytreatment with peroxy acids such m-chloroperoxybenzoic acid. Manyalkenes are commercially available or readily prepared from ketones(XXIX) by methods described in the literature (such as wittig reaction)and known to those skilled in art.

The epoxides (XXX) are used to prepare thioalcohol compounds of formula(XXXII). These can be conveniently prepared by a variety of methodsfamiliar to those skilled in the art. The epoxide (XXX) is treated witha pretreated mixture of sodium sulfide and acids such as p-toluenesulfonic acid in polar protic solvent such as methanol for 0.5-4 hoursat a temperature of 0-25° C. to provide the Thioalcohol (XXXII). Anothercommon route to prepare Thioalcohols (XXXII) is by treating epoxide(XXX) with triphenylsilane thiol, tertiary anine bases such as triethylamine and in polar protic solvent such as methanol for 0.54 hours atambient temperatures.

Thioalcohols (XXXII) are used to prepare 1,2-quinone alcohol (XXXIII).These can be conveniently prepared by methods familiar to those skilledin the art. Thioalcohol (XXXII) is treated with 1,2-quinones (VII),bases such as potassium carbonate and solvents such as tetrahydrofuranambient temperatures to provide the 1,2-quinone alcohols with formula(XXXIII). Alternatively bases such as triethylamine, sodium carbonate,cesium carbonate and solvents such as acetonitrile dichloromethane canalso be utilized.

1,2-Quinone alcohols (XXXIII) are used to prepare spiro-1,2-quinonecompounds with formula (XXXIV). These can be conveniently prepared bymethods familiar to those skilled in the art. 1,2-Quinone alcohols withformula (XXXIII) are treated with acid such as trifluoroacetic acid andsolvents such as dichloromethane in open air at ambient temperature for24-96 hours. Alternatively acids such as p-toluenesulfonic acid can alsobe used and air or oxygen can also be bubbled through the reaction.

The compounds of the present invention having the formula (Ib) where J₂and J₃ can be protecting group such as dioxolane ring, ketone or when J₂is hydrogen, J₃ is phenyl or N-J₁, and J₁ is a protecting group such astert-butyl carbamate (t-BOC) or selected from additional groupsdescribed in the detailed description of the invention, can beconveniently prepared as shown in Scheme 9 and 15.

Epoxide compounds (XXXVI) may be conveniently prepared from ketones(XXXV). Trimethylsulfoxnium ylide is prepared by treatingtrimethlylsulfoxonium iodide with bases such as sodium hydride in apolar solvent such as anhydrous dimethylsulfoxide. Other bases such aspotassium t-butoxide may also be used instead of sodium hydride. Thetrimethlylsulfoxonium ylide is treated with ketone (XXXV) at 0° C.initially and the reaction warmed to room temperature for 4-24 hours toprovide epoxide (XXXVI). Many ketones are commercially available orreadily prepared by methods described in the literature and known tothose skilled in art. Alternatively, the epoxide (XXXVI) can also beconveniently prepared from alkenes (XXXVII) by treatment with peroxyacids such m-chloroperoxybenzoic acid. Many alkenes are commerciallyavailable or readily prepared from ketone (XXXV) by methods described inthe literature (such as wittig reaction) and known to those skilled inart.

The epoxides (XXXVI) are used to prepare thioalcohol compounds offormula (XXXVIII). These can be conveniently prepared by a variety ofmethods familiar to those skilled in the art. The epoxide (XXXVI) istreated with a pretreated mixture of sodium sulfide and acids such asp-toluene sulfonic acid in polar protic solvent such as methanol for0.5-4 hours at a temperature of 0-25° C. to provide the thioalcohol(XXXVIII). A preferred common route to prepare thioalcohols (XXXVIII)where J₂ and J₃ are a part of the dioxolane ring, which is an acidsensitive moiety is by treating epoxide (XXXVI) with triphenylsilanethiol, tertiary amine bases such as triethyl amine and in polar proticsolvent such as methanol for 0.5-4 hours at ambient temperatures.

The thioalcohols (XXXVIII) are used to prepare 1,2-quinone alcoholcompounds of formula (XXXIX). These can be conveniently prepared bymethods familiar to those skilled in the art. Thioalcohol (XXXVIII) istreated with 1,2-quinones (VII), bases such as potassium carbonate andsolvents such as tetrahydrofuran for 0.5-4 hours at ambient temperaturesto provide the 1,2-quinone alcohols with formula (XXXIX). Alternativelybases such as triethylamine, sodium carbonate, cesium carbonate andsolvents such as acetonitrile dichloromethane can also be utilized.

1,2-Quinone alcohols (XXXIX) are used to prepare spiro-1,2-quinonecompounds (XXXX). These can be conveniently prepared by methods familiarto those skilled in the art. 1,2-Quinone alcohols (XXXIX) are treatedwith acid such as trifluoroacetic acid and solvents such asdichloromethane in open air at ambient temperature for 24-96 hours toprepare spiro-1,2-quinone (XXXX). Alternatively acids such asp-toluenesulfonic acid can also be used and air or oxygen can also bebubbled through the reaction. In the reaction where J₂ and J₃ isdioxolane protecting group, spiro-1,2-quinone ketone (XXXX) is alsoformed. In the reaction where J₂ is hydrogen, J₃ is N-J₁ where J₁ is aprotecting group such as tert-butyl carbamate (t-BOC), the crudespiro-1,2-quinone is isolated in which J₁ is hydrogen. The crudespiro-1,2-quinone where J₁ is hydrogen is treated with di-tert-butyldicarbonate in bases such as aqueous sodium bicarbonate, solvent such asdichloromethane for 0.25-4 hours at ambient temperature to provide thespiro-1,2-quinones (XXXX) where J₁ is tert-butyl carbamate (t-BOC)protecting group.

As shown in Scheme 16, spiro-1,2-quinone alcohol (XXXXI) can beconveniently prepared by treating spiro-1,2-quinone ketone (XXXX) withreducing agents such as sodium borohydride in solvents such as methanolat ambient temperatures for 4-24 hours. Alternatively reducing agentssuch as sodium triacetoxyborohydride in solvents such astetrahydrofuran, dichloromethane can also be used to preparespiro-1,2-quinone alcohol with formula (XXXXI)

Compounds of formula (XXXXII) can be prepared as shown in Scheme 17.Spiro-1,2-quinones (XXXXII) can be prepared by treatingspiro-1,2-quinones (XXXX) where and J₁ is a protecting group such ast-butyl carbamate (t-BOC) with acids such as a solution of hydrogenchloride gas in solvents such as ethyl acetate, 1,2-dioxane, diethylether at ambient temperature for 1-24 hours to give the product as anhydrochloride salt. Alternatively trifluoroacetic acid in solvents suchas dichloromethane can also be used in the above reaction. The productspiro-1,2-quinones (XXXXII) can be isolated as free base, hydrochlorideor trifluoroacetic acid salt. To obtain the free base an aqueous workupwith sodium bicarbonate is carried out on either acid salt. The abovecondition also describes the method to deprotect amines protected witht-butoxycarbamoyl (t-BOC) group.

Scheme 18 illustrates a variety of chemical transformation ofspiro-1,2-quinone (XXXXI) to provide compounds (XXXXII-XXXXIII). Thefollowing methods are provided by way of exemplification. Furthermore,the spiro-1,2-quinone (XXXXII) can also be functionalized to preparecompounds with functional groups in an analogous fashion as illustratedin Scheme 9. Alternative methods may be employed and are described inreference text's such as Comprehensive Organic Transformations, RichardC. Larock, Second Edition, Wiley—VCH, 1999; Protective Groups in OrganicSynthesis, Third Edition, Theodora W. Greene and Peter M. Wuts, WileyInterscience, 1999; The Practice of Peptide Synthesis, M. Bodanszky andA. Bodanzsky, Springer-Verlag, 1984.

The spiro-1,2-quinone amides (XXXXII) can be conveniently prepared bytreating spiro-1,2-quinone (XXXXI) with acid chlorides such asm-trifluoromethylbenzoyl chlorides in presence of tertiary amine basessuch as triethylamine, diisopropylethyl amine and solvents such asdichloromethane at ambient temperature for 1-12 hours. Many acidchlorides are commercially available or readily prepared by methodsdescribed in the literature and known to those skilled in art.

Alternatively spiro-1,2-quinone amides (XXXXIII) can be convenientlyprepared by treating spiro-1,2-quinone (XXXII) with carboxylic acidswith formula in presence of amide coupling agents such as HBTU(O-(benzotriazo-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate),tertiary amine bases such as dimethylaminopyridine and solvents such asdimethylformamide at ambient temperature for 4-24 hours. Alternativelyamide coupling agents such as DCC (dicylcohexycarbodiimide), BOP((benzotriazo-1-yloxy)tris(dimethylamino) phosphoniumhexafluorophosphate, EDCI.HCl (1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride), DMC(2-chloro-1,3-dimethylimidazolinium chloride) and tertiary amines basessuch as triethylamine, diisopropylethyl amine can also be used. Manycarboxylic acids are commercially available or readily prepared bymethods described in the literature and known to those skilled in art.

Spiro-1,2-quinone carbamates (XXXXIV) can be conveniently prepared bytreating spiro-1,2-quinone (XXXXII) with carbamoyl chlorides such as3-(trifluoromethyl)phenyl chloroformate, bases such as triethylamine,diisopropylethyl amine, aqueous sodium carbonate in solvents such asethyl acetate, dichloromethane at ambient temperature for 1-12 hours.Many carbamates are commercially available or readily prepared bymethods described in the literature and known to those skilled in art.

Compounds encompassed in the invention can be produced according to thisor other synthetic processes without departing from the spirit oressential characteristics of the invention. All changes that come withinthe meaning and range of equivalency of the compounds are intended to beembraced herein. Thus, it is expected that one of ordinary skill in theart would know how to alter the synthetic schemes illustrated herein soas to produce a desired substitution pattern on a compound, produce anincreased or decreased product yield, minimize reaction side products,eliminate the use of dangerous or toxic chemical reactants, and/or toproduce a desired amount of product (e.g., scale-up reaction size forcommercial manufacture), and the like.

The present invention further provides a compound prepared by one of thesynthetic processes disclosed herein, such as those disclosed in theExamples.

3. Methods of Treatment

The present invention also provides a method for the treatment of a cellproliferative disorder in a mammal comprising administering to a mammalin need of such treatment, a therapeutically effective amount of acompound of Formula I. The invention further provides the use of acompound of Formula I for the preparation of a medicament useful for thetreatment of a cell proliferative disorder. In one embodiment, theinvention provides for the treatment of cancer or precancerousconditions in a mammal comprising administering to a mammal in need ofsuch treatment, a therapeutically effective amount of a compound ofFormula I. The mammal can be e.g., any mammal, e.g., a human, a primate,mouse, rat, dog, cat, cow, horse, pig. For example, the mammal is ahuman.

An effective amount of a compound of Formula I is used in a method totreat a cell proliferative disorder in a mammal without affecting normalcells of the mammal. For example, a therapeutically effective amount ofa compound of Formula I is used in a method for treating cancer in amammal by inducing cell death in cancer cells without affecting normalcells in the normal. Cell death can occur by either apoptosis ornecrosis mechanisms. In another example, administration of atherapeutically effective amount of a compound of Formula I inducessustained (non-transient) activity (e.g. elevation of the level) of acheckpoint molecule in abnormally proliferating cells without affectingcheckpoint molecule activity in normal cells. For example,administration of a therapeutically effective amount of a compound ofFormula I induces activation of E2F1 checkpoint pathway in abnormallyproliferating cells without significantly affecting normal cells. Inanother example, administration induces sustained E2F pathway activity(e.g. elevation of E2F levels) in cancer cells without affecting E2Fpathway activity (e.g. E2F levels) in normal cells. Methods of measuringinduction of E2F activity and elevation of E2F levels are as shown in Liet al., (2003) Proc Natl Acad Sci USA. 100(5): 2674-8. In anotherexample, administration of a therapeutically effective amount of acompound of Formula I induces cell death in abnormally proliferatingcells without inducing cell death in normal cells.

The invention also provides a method of protecting against a cellproliferative disorder in a mammal by administering a therapeuticallyeffective amount of a compound of Formula I to a mammal. The inventionalso provides the use of a compound of Formula I for the preparation ofa medicament useful for the prevention of a cell proliferative disorder.In one embodiment, the invention provides for the prevention of cancerin a mammal comprising administering to a mammal in need of suchtreatment, a therapeutically effective amount of a compound of FormulaI.

The compounds of the invention are administered in the form ofpharmaceutical compositions, e.g., as described herein.

As used herein, a “subject” can be any mammal, e.g., a human, a primate,mouse, rat, dog, cat, cow, horse, pig, sheep, goat, camel. In apreferred aspect, the subject is a human.

As used herein, a “subject in need thereof” is a subject having a cellproliferative disorder, or a subject having an increased risk ofdeveloping a cell proliferative disorder relative to the population atlarge. In one aspect, a subject in need thereof has a precancerouscondition. In a preferred aspect, a subject in need thereof has cancer.

As used herein, the term “cell proliferative disorder” refers toconditions in which the unregulated and/or abnormal growth of cells canlead to the development of an unwanted condition or disease, which canbe cancerous or non-cancerous, for example a psoriatic condition. Asused herein, the term “psoriatic condition” refers to disordersinvolving keratinocyte hyperproliferation, inflammatory cellinfiltration, and cytokine alteration.

In one embodiment, the cell proliferation disorder is cancer. As usedherein, the term “cancer” includes solid tumors, such as lung, breast,colon, ovarian, prostate, malignant melanoma, non-melanoma skin cancers,as well as hematologic tumors and/or malignancies, such as childhoodleukemia and lymphomas, multiple myeloma, Hodgkin's disease, lymphomasof lymphocytic and cutaneous origin, acute and chronic leukemia such asacute lymphoblastic, acute myelocytic or chronic myelocytic leukemia,plasma cell neoplasm, lymphoid neoplasm and cancers associated withAIDS.

In addition to psoriatic conditions, the types of proliferative diseaseswhich may be treated using the compositions of the present invention areepidermic and dermoid cysts, lipomas, adenomas, capillary and cutaneoushemangiomas, lymphangiomas, nevi lesions, teratomas, nephromas,myofibromatosis, osteoplastic tumors, and other dysplastic masses andthe like. In one embodiment, proliferative diseases include dysplasiasand disorders of the like.

As used herein, “monotherapy” refers to administration of a singleactive or therapeutic compound to a subject in need thereof. Preferably,monotherapy will involve administration of a therapeutically effectiveamount of an active compound. For example, cancer monotherapy with oneof the compound of the present invention, or a pharmaceuticallyacceptable salt, prodrug, metabolite, analog or derivative thereof, to asubject in need of treatment of cancer. Monotherapy may be contrastedwith combination therapy, in which a combination of multiple activecompounds is administered, preferably with each component of thecombination present in a therapeutically effective amount. In oneaspect, monotherapy with a compound of the present invention is moreeffective than combination therapy in inducing a desired biologicaleffect.

As used herein, “treating” describes the management and care of apatient for the purpose of combating a disease, condition, or disorderand includes the administration of a compound of the present inventionto prevent the onset of the symptoms or complications, alleviating thesymptoms or complications, or eliminating the disease, condition ordisorder.

In one aspect, treating cancer results in a reduction in size of atumor. In another aspect, treating cancer results in a reduction intumor volume. In another aspect, treating cancer results in a decreasein number of tumors. In another aspect, treating cancer results in adecrease in number of metastatic lesions in other tissues or organsdistant from the primary tumor site. In another aspect, treating cancerresults in an increase in average survival time of a population oftreated subjects in comparison to a population receiving carrier alone.In another aspect, treating cancer results in an increase in averagesurvival time of a population of treated subjects in comparison to apopulation of untreated subjects. In another aspect, treating cancerresults in increase in average survival time of a population of treatedsubjects in comparison to a population receiving monotherapy with a drugthat is not a compound of the present invention, or a pharmaceuticallyacceptable salt, prodrug, metabolite, analog or derivative thereof. Inanother aspect, treating cancer results in a decrease in the mortalityrate of a population of treated subjects in comparison to a populationreceiving carrier alone. In another aspect, treating cancer results in adecrease in the mortality rate of a population of treated subjects incomparison to an untreated population. In a further aspect, treatingcancer results a decrease in the mortality rate of a population oftreated subjects in comparison to a population receiving monotherapywith a drug that is not a compound of the present invention, or apharmaceutically acceptable salt, prodrug, metabolite, analog orderivative thereof. In another aspect, treating cancer results in adecrease in tumor growth rate. In another aspect, treating cancerresults in a decrease in tumor regrowth.

In another aspect, treating or preventing a cell proliferative disorderresults in a reduction in the rate of cellular proliferation. In anotheraspect, treating or preventing a cell proliferative disorder results ina reduction in the proportion of proliferating cells. In another aspect,treating or preventing a cell proliferative disorder results in adecrease in size of an area or zone of cellular proliferation. Inanother aspect, treating or preventing a cell proliferative disorderresults in a decrease in the number or proportion of cells having anabnormal appearance or morphology.

In additional aspects, β-lapachone, or a pharmaceutically acceptablesalt, metabolite, analog or derivative thereof, can be administered incombination with a chemotherapeutic agent. Exemplary chemotherapeuticswith activity against cell proliferative disorders are known to those ofordinary skill in the art, and may be found in reference texts such asthe Physician's Desk Reference, 59^(th) Edition, Thomson PDR (2005). Forexample, the chemotherapeutic agent can be a taxane, an aromataseinhibitor, an anthracycline, a microtubule targeting drug, atopoisomerase poison drug, a targeted monoclonal or polyclonal antibody,an inhibitor of a molecular target or enzyme (e.g., a kinase inhibitor),or a cytidine analogue drug. In preferred aspects, the chemotherapeuticagent can be, but is not restricted to, tamoxifen, raloxifene,anastrozole, exemestane, letrozole, cisplatin, carboplatin, TAXOL®(paclitaxel), cyclophosphamide, lovastatin, minosine, GEMZAR®(gemcitabine HCl), araC, 5-fluorouracil (5-FU), methotrexate (MTX),TAXOTERE® (docetaxel), ZOLADEX® (goserelin), vincristin, vinblastin,nocodazole, teniposide, etoposide, epothilone, navelbine, camptothecin,daunonibicin, dactinomycin, mitoxantrone, amsacrine, doxorubicin(adriamycin), epirubicin, idarubicin, or GLEEVEC® (imatanib), IRESSA®(gefitinib), TARCEVA® (erlotinib), NEXAVAR® (sorafenib), SUTENT®(sunitinib malate), HERCEPTIN® (trastuzumab), RITUXAN® (Rituximab),ERBITUX® (cetuximab), AVASTIN® (bevacizumab), or agents listed inhttp://www.cancer.org/docroot/cdg/cdg_(—)0.asp. In another aspect, thechemotherapeutic agent can be a cytokine such as G-CSF (granulocytecolony stimulating factor). In another aspect, β-lapachone, or apharmaceutically acceptable salt, metabolite, analog or derivativethereof may be administered in combination with radiation therapy. Inyet another aspect, β-lapachone, or a pharmaceutically acceptable salt,metabolite, analog or derivative thereof may be administered incombination with standard chemotherapy combinations such as, but notrestricted to, CMF (cyclophosphamide, methotrexate and 5-fluorouracil),CAF (cyclophosphamide, adriamycin and 5-fluorouracil), AC (adriamycinand cyclophosphamide), FEC (5-fluorouracil, epirubicin, andcyclophosphamide), ACT or ATC (adriamycin, cyclophosphamide, andpaclitaxel), or CMFP (cyclophosphamide, methotrexate, 5-fluorouracil andprednisone).

4. The Pharmaceutical Compositions and Formulations

A “pharmaceutically acceptable salt” or “salt” of the disclosed compoundis a product of the disclosed compound that contains an ionic bond, andis typically produced by reacting the disclosed compound with either anacid or a base, suitable for administering to a subject.Pharmaceutically acceptable salt can include, but is not limited to,acid addition salts including hydrochlorides, hydrobromides, phosphates,sulphates, hydrogen sulphates, alkylsulphonates, arylsulphonates,acetates, benzoates, citrates, maleates, fumarates, succinates,lactates, and tartrates; alkali metal cations such as Na, K, Li, alkaliearth metal salts such as Mg or Ca, or organic amine salts.

A “pharmaceutical composition” is a formulation containing the disclosedcompounds in a form suitable for administration to a subject. In oneembodiment, the pharmaceutical composition is in bulk or in unit dosageform. The unit dosage form is any of a variety of forms, including, forexample, a capsule, an IV bag, a tablet, a single pump on an aerosolinhaler, or a vial. The quantity of active ingredient (e.g., aformulation of the disclosed compound or salts thereof) in a unit doseof composition is an effective amount and is varied according to theparticular treatment involved. One skilled in the art will appreciatethat it is sometimes necessary to make routine variations to the dosagedepending on the age and condition of the patient. The dosage will alsodepend on the route of administration. A variety of routes arecontemplated, including oral, pulmonary, rectal, parenteral,transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal,intranasal, and the like. Dosage forms for the topical or transdermaladministration of a compound of this invention include powders, sprays,ointments, pastes, creams, lotions, gels, solutions, patches andinhalants. In one embodiment, the active compound is mixed under sterileconditions with a pharmaceutically acceptable carrier, and with anypreservatives, buffers, or propellants that are required.

The present invention also provides pharmaceutical formulationscomprising a compound of Formula I in combination with at least onepharmaceutically acceptable excipient or carrier. As used herein,“pharmaceutically acceptable excipient” or “pharmaceutically acceptablecarrier” is intended to include any and all solvents, dispersion media,coatings, antibacterial and antifungal agents, isotonic and absorptiondelaying agents, and the like, compatible with pharmaceuticaladministration. Suitable carriers are described in “Remington: TheScience and Practice of Pharmacy, Twentieth Edition.” LippincottWilliams & Wilkins, Philadelphia, Pa., which is incorporated herein byreference. Examples of such carriers or diluents include, but are notlimited to, water, saline, Ringer's solutions, dextrose solution, and 5%human serum albumin. Liposomes and non-aqueous vehicles such as fixedoils may also be used. The use of such media and agents forpharmaceutically active substances is well known in the art. Exceptinsofar as any conventional media or agent is incompatible with theactive compound, use thereof in the compositions is contemplated.Supplementary active compounds can also be incorporated into thecompositions.

Methods for formulation are disclosed in PCT International ApplicationPCT/US02/24262 (WO03/011224), U.S. Patent Application Publication No.2003/0091639 and U.S. Patent Application Publication No. 2004/0071775,each of which is incorporated by reference herein.

A compound of Formula I is administered in a suitable dosage formprepared by combining a therapeutically effective amount (e.g., anefficacious level sufficient to achieve the desired therapeutic effectthrough inhibition of tumor growth, killing of tumor cells, treatment orprevention of cell proliferative disorders, etc.) of a compound ofFormula I (as an active ingredient) with standard pharmaceuticalcarriers or diluents according to conventional procedures (i.e., byproducing a pharmaceutical composition of the invention). Theseprocedures may involve mixing, granulating, and compressing ordissolving the ingredients as appropriate to attain the desiredpreparation. In another embodiment, a therapeutically effective amountof a compound of Formula I is administered in a suitable dosage formwithout standard pharmaceutical carriers or diluents.

Pharmaceutically acceptable carriers include solid carriers such aslactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia,magnesium stearate, stearic acid and the like. Exemplary liquid carriersinclude syrup, peanut oil, olive oil, water and the like. Similarly, thecarrier or diluent may include tune-delay material known in the art,such as glyceryl monostearate or glyceryl distearate, alone or with awax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate orthe like. Other fillers, excipients, flavorants, and other additivessuch as are known in the art may also be included in a pharmaceuticalcomposition according to this invention.

The pharmaceutical compositions containing active compounds of thepresent invention may be manufactured in a manner that is generallyknown, e.g., by means of conventional mixing, dissolving, granulating,dragee-making, levigating, emulsifying, encapsulating, entrapping, orlyophilizing processes. Pharmaceutical compositions may be formulated ina conventional manner using one or more physiologically acceptablecarriers comprising excipients and/or auxiliaries which facilitateprocessing of the active compounds into preparations that can be usedpharmaceutically. Of course, the appropriate formulation is dependentupon the route of administration chosen.

A compound or pharmaceutical composition of the invention can beadministered to a subject in many of the well-known methods currentlyused for chemotherapeutic treatment. For example, for treatment ofcancers, a compound of the invention may be injected directly intotumors, injected into the blood stream or body cavities or taken orallyor applied through the skin with patches. For treatment of psoriaticconditions, systemic administration (e.g., oral administration), ortopical administration to affected areas of the skin, are preferredroutes of administration. The dose chosen should be sufficient toconstitute effective treatment but not so high as to cause unacceptableside effects. The state of the disease condition (e.g., cancer,psoriasis, and the like) and the health of the patient should be closelymonitored during and for a reasonable period after treatment.

EXAMPLES

Examples are provided below to further illustrate different features ofthe present invention. The examples also illustrate useful methodologyfor practicing the invention. These examples do not limit the claimedinvention.

Example 1 Procedure A

E1.1. Synthesis of tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate(Compound 1)

A mixture of trimethylsulfoxonium iodide (65.2 g, 29.6 mmol) andanhydrous DMSO (300 ml) was stirred at room temperature for 1 hour undera nitrogen atmosphere. The reaction was then cooled to 0° C. and NaH(60% in mineral oil) (14.2 g, 35.5 mmol) was added in small portionsover the course of 1 hour. The reaction mixture was allowed to warn toroom temperature and stirred for 4 hours. The reaction mixture was thencooled to 0° C., tert-butyl 4-oxo-1-piperidinecarboxylate (59.0 g, 29.6mmol) added, then allowed to react at room temperature for 16 hours. Thereaction mixture was then poured onto 1.2 liters of ice water andextracted with ether (4×400 ml). The organic layers were washed withwater (2×500 ml) and brine (2×500 ml). The organic extract was driedwith Na₂SO₄ and concentrated under reduced pressure. The crude productwas purified by flash column chromatography (SiO₂, 5% EtOAc in hexanesto 40% EtOAc in hexanes) to afford the product as white crystallinesolid (35.3 g, 56%). M.p.=48-50° C.; 400 MHz ¹H NMR (CDCl₃) δ: 3.77-3.68(m, 2H), 3.45-3.36 (m, 2H), 2.68 (s, 2H), 1.83-1.74 (m, 2H), 1.5-1.4 (m,11H); LCMS: 214 [M+H].

E1.2. Synthesis of tert-butyl 1-oxa-6-azaspiro[2.6]nonane-6-carboxylate(Compound 2)

Compound 2 was synthesized using tert-butyl 4-oxoazepane-1-carboxylateusing conditions outlines in procedure A. 400 MHz ¹H NMR (CDCl₃) δ:3.70-3.50 (m, 2H), 3.36-3.28 (m, 2H), 2.66-2.61 (m, 2H), 2.00-1.67 (m,6H), 1.47 (s, 9H).

E1.3. Synthesis of tert-butyl 1-oxa-5-azaspiro[2.5]octane-5-carboxylate(Compound 3)

Compound 3 was synthesized using tert-butyl3-oxopiperidine-1-carboxylate using conditions outlines in procedure A.400 MHz ¹H NMR (CDCl₃) δ: 3.47-3.44 (m, 3H), 3.37-3.33 (m, 1H), 2.76(brs, 1H), 2.66 (d, J=4.4 Hz, 1H), 1.9-1.79 (m, 1H), 1.77-1.61 (m, 3H),1.4 (s, 9H).

Example 2 Procedure B

E2.1. Synthesis of tert-butyl4-hydroxy-4-(mercaptomethyl)piperidine-1-carboxylate (Compound 4)

To a mixture of tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate(35.3 g, 16.55 mmol) and triphenylsilanethiol (48.4 g, 16.55 mmol) inanhydrous methanol (1.0 L) was added triethylamine (23.1 ml, 16.55 mmol)drop-wise over the course of 30 minutes. The reaction was stirred for 1hour at room temperature and the methanol was evaporated under reducedpressure. The crude product was purified by flash column chromatography(SiO₂, 5% EtOAc in hexanes to 40% EtOAc in hexanes) to afford 81% (33.1g) pure final product. M.p.=54-55° C.; 400 MHz ¹H NMR (CDCl₃) δ:3.97-3.78 (m, 2H), 3.19-3.08 (m, 2H), 2.61 (d, J=4.4 Hz, 2H), 1.70-1.55(m, 2H), 1.50-1.38 (m, 11H); LCMS: 248 [M+H].

Example 3 Procedure C

E3.1. Synthesis of tert-butyl4-hydroxy-4-(mercaptomethyl)piperidine-1-carboxylate (Compound 4)

Sodium sulfide nonahydrate (60 g, 0.25 mol) was dissolved in MeOH (1.25L), and the resulting solution was degassed by applying vacuum andfilling nitrogen three times. The solution was then cooled to 0° C. withan ice-water bath. To the above solution was added p-toluenesulfonicacid hydrate (76 g, 0.4 mol) and the resulting mixture was stirred at 0°C. for 10 min. A yellowish colored solution was formed. The tert-butyl1-oxa-6-azaspiro[2.5]octane-6-carboxylate (21.2 g, 0.1 mol) was added tothe reaction mixture and stirred at 0° C. for 1 h and then at roomtemperature for 1.5 h. Saturated sodium bicarbonate solution (200 mL)was added to the reaction, and the methanol was evaporated under reducedpressure. To the residue was added water (500 mL) and extracted withEtOAc (1×400 mL and 2×250 mL), the combined organic layer was washedwith brine (250 mL) and dried over sodium sulfate. After concentration,the crude product (26.2 g) was obtained as an oil. The crude product waspurified by flash column chromatography (SiO₂, 5% to 40% EtOAc inhexanes) to afford the product as a white solid. (19.2 g, 78%).M.p.=54-55° C.; 400 MHz ¹H NMR (CDCl₃) δ: 3.97-3.80 (m, 2H), 3.19-3.08(m, 2H), 2.61 (d, J=4.4 Hz, 2H), 2.22 (s, 1H), 1.68-1.60 (m, 2H),1.50-1.40 (m, 11H); LCMS: 248 [M+H].

E3.2. Synthesis of tert-butyl4-hydroxy-4-(mercaptomethyl)azepane-1-carboxylate (Compound 5)

Compound 5 was synthesized using tert-butyl1-oxa-6-azaspiro[2.6]nonane-6-carboxylate using conditions outlined inprocedure C.

E3.3. Synthesis of tert-butyl3-hydroxy-3-(mercaptomethyl)piperidine-1-carboxylate (Compound 6)

Compound 6 was synthesized using tert-butyl1-oxa-5-azaspiro[2.5]octane-5-carboxylate and conditions outlined inprocedure C.

Example 4 Procedure D

E4.1. Synthesis of 6-chloronaphthalene-1,2-dione (Compound 7)

To a solution of benzeneselenic anhydride (3.18 g, 8.8 mmol) intetrahydrofuran (30 ml), which had been heated to 70° C. was added asolution of 6-chloro-1-naphthol (1.5 g, 8.4 mmol) in tetrahydrofuran (5ml). The reaction was maintained at 70° C. for 15 minutes. The mixturewas then concentrated under reduced pressure. The residue was suspendedin hexanes (100 ml) and filtered. This was repeated 5 times. The residuewas dissolved in dichloromethane (100 ml), filtered and concentratedunder reduced pressure to afford the product as an orange solid (1.33 g,82%); 400 MHz ¹H NMR (CDCl₃) δ: 8.06 (d, J=8.4 Hz, 1H), 7.49 (dd, J=2and 8.4 Hz. 1H), 7.41-7.38 (m, 2H), 6.50 (d, J=10 Hz, 1H).

E4.2. Synthesis of 7-methoxynaphthalene-1,2-dione (Compound 8)

Compound 8 was synthesized using 7-methoxy-2-naphthol and conditionsoutlined in procedure D. M.p.=78-80° C.; 400 MHz ¹H NMR (DMSO-d₆) δ:7.86-7.42 (m, 4H), 6.37 (d, J=9.6 Hz, 1H), 3.93 (s, 3H); LCMS: 189 [M+H]

E4.3. Synthesis of 6-fluoronaphthalene-1,2-dione (Compound 9)

Compound 9 was synthesized using 6-fluoro-1-naphthol and conditionsoutlined in procedure D. 400 MHz ¹H NMR (CDCl₃) δ: 8.18-8.15 (dd,J=8.60, 5.47 Hz, 1H), 7.41-7.38 (d, J=10.17 Hz, 1H), 7.21-7.16 (m, 1H),7.09-7.06 (dd, J=8.21, 2.34 Hz, 1H), 6.51-6.49 (d, J=10.17 Hz, 1H).

E4.4. Synthesis of 6-bromonaphthalene-1,2-dione (Compound 10)

Compound 10 was synthesized using 6-bromo-1-naphthol and conditionsoutlined in procedure D.

E4.5. Synthesis of 6-methoxy-1,2-dione (Compound 11)

Compound 11 was synthesized using 6-methoxy-1-naphthol and conditionsoutlined in procedure D.

Example 5 Procedure E

E5.1. Synthesis of tert-butyl4-{[(3,4-dioxo-3,4-dihydronaphthalen-1-yl)thio]methyl}-4-hydroxypiperidine-1-carboxylate(Compound 12)

To a solution of naphthalene-1,2-dione (3.2 g, 2.02 mmol) and tert-butyl4-hydroxy-4-(mercaptomethyl)piperidine-1-carboxylate (5.0 g, 2.02 mmol)in anhydrous acetonitrile (400 ml) was added triethylamine (2.82 ml,2.02 mmol). The reaction mixture was allowed to stir for 1 hour at roomtemperature and the solvents were evaporated under reduced pressure. Thecrude product was purified by flash column chromatography (SiO₂, 40%EtOAc in hexanes to 70% EtOAc in hexanes). Fractions containing theproduct were concentrated and tritrated with ethyl acetate/ether toafford the desired product as a red solid (2.4 g, 29%). M.p.=156-157°C.; 400 MHz ¹H NMR (CDCl₃) δ: 8.17-8.12 (m, 1H), 7.87-7.83 (m, 1H),7.69-7.62 (m, 1H), 7.59-7.52 (m, 1H), 6.49 (s, 1H), 4.0-3.85 (m, 2H),3.25-3.14 (m, 4H), 1.84-1.78 (m, 2H), 1.76-1.66 (m, 2H), 1.47 (s, 9H);LCMS: 404 [M+H].

E5.2. Synthesis ofspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidinium]-5,6-dione chloride(Compound 13)

To a solution of tert-butyl4-{[(3,4-dioxo-3,4-dihydronaphthalen-1-yl)thio]methyl}-4-hydroxypiperidine-1-carboxylate(3.8 g, 0.942 mmol) in 50 ml dichloromethane which was cooled to 0° C.was added trifluoroacetic acid (200 ml). The reaction mixture wasstirred at room temperature for 30 hours and the solvent removed underreduced pressure. The mixture was dissolved in dichloromethane (150 ml)and pouted over a 0° C. mixture of saturated sodium carbonate (500 ml)and water (200 ml). Methanol (500 ml) was then added to the reactionmixture and allowed to stir overnight. The mixture was extracted withdichloromethane (4×400 ml). The organic extracts were combined andwashed with a mixture of 2.0M sodium carbonate and brine (5×500 ml). Theorganic layer was separated, dried with Na₂SO₄, and concentrated underreduced pressure to give a purple solid. To a stirred solution of thepurple solid in dichloromethane (100 ml), 4.0 M HCl in dioxane (20 ml)was added dropwise. The precipitate was filtered, washed withdichloromethane and ether, and recrystallized from ethanol to give apurple crystalline solid (1.84 g, 58%). M.p.=229-232° C.; 400 MHz ¹H NMR(DMSO-d₆) δ: 9.19 (br, s, 2H), 7.90-7.86 (m, 1H), 7.84-7.80 (m, 1H),7.76-7.71 (m, 1H), 7.58-7.53 (m, 1H), 3.33-3.25 (m, 2H), 3.16-3.07 (m,4H), 2.22-2.15 (m, 2H), 2.20-1.50 (m, 2H); LCMS: 302 [M+H].

E5.3. Synthesis ofspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidinium]-5,6-dionecis-2-carboxycyclohexanecarboxylate (Compound 14)

To a mixture ofspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (0.5 g,1.66 mmol) and acetonitrile (20 ml) which had been preheated to 80° C.was added a preheated (80° C.) solution ofcis-cyclohexane-1,2-dicarboxylic acid (0.286 ml, 1.66 mmol) inacetonitrile (20 ml). The reaction mixture was stirred overnight at 80°C. The resulting purple precipitate was filtered, washed withacetonitrile, and dried under reduced pressure to afford the product asa purple solid (0.472 g, 60%). M.p.=204-207° C.; 400 MHz ¹H NMR(DMSO-d₆) δ: 7.90-7.87 (m, 1H), 7.83-7.81 (m, 1H), 7.78-7.73 (m, 1H),7.58-7.54 (m, 1H), 3.16-3.11 (m, 4H), 3.07-3.00 (m, 2H), 2.53-2.48 (m,2H), 2.11-2.05 (m, 2H), 1.88-1.75 (m, 4H), 1.52-1.40 (m, 4H), 1.33-1.29(m, 2H); LCMS: 302 [M+H].

E5.4. Synthesis ofspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidinium]-5,6-dionetrains-2-carboxycyclohexanecarboxylate (Compound 15)

Compound 15 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,trans-cyclohexane-1,2-dicarboxylic acid and conditions outlined forcompound 14. M.p.=208-211° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 7.90-7.87 (m,1H), 7.82-7.73 (m, 2H), 7.58-7.53 (m, 1H), 3.06 (s, 2H), 2.96-2.86 (m,4H), 2.29-2.26 (m, 2H), 1.98-1.91 (m, 4H), 1.77-1.65 (m, 4H), 1.23-1.17(m, 4H); LCMS: 302 [M+H].

Example 6 Procedure F

E6.1. Synthesis ofspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (Compound16)

Step (i): To a 2 L round-bottomed flask containing the crude tert-butyl4-hydroxy-4-(mercaptomethyl)piperidine-1-carboxylate (25.5 g, 0.1 mol)was added THF (1.1 L) followed by naphthalene-1,2-dione (13.0 g, 85mmol) and granular K₂CO₃ (21 g). The reaction was allowed to proceed for1 h at room temperature. The reaction mixture was filtered to remove allsolids and the filtrate concentrated under reduced pressure. The cruderesidue obtained was used in step (ii) without any further purification.

Step (ii): The crude residue was dissolved in dichloromethane (400 mL)and trifluoroacetic acid (250 mL) was added in three portions. Thereaction mixture was allowed to proceed at room temperature in an openflask. After the reaction was stirred overnight, air was bubbled intothe reaction and the reaction was continued to stir for additional 48 h.The solvent was then removed under reduced pressure and the residue wasdissolved in 1:9 methanol/dichloromethane (800 mL). The organics wereextracted twice with water (2×400 mL). The pH of the combined aqueousextracts were adjusted to pH 8 using saturated NaHCO₃. The aqueous layerwas then extracted with 1:9 methanol/dichloromethane (5×300 mL). Thecombined organic extracts was washed with brine, dried (with Na₂SO₄),filtered and concentrated under reduced pressure to afford the productas a dark purple solid (combined yield for two steps: 12.4 g, 51%).M.p.=234-240° C.; 400 MHz ¹H NMR (CDCl₃) δ: 8.08-8.03 (m, 1H), 7.82-7.78(m, 1H), 7.68-7.63 (m, 1H), 7.51-7.46 (m, 1H), 3.12-3.00 (m, 4H), 2.94(s, 2H), 2.13-2.06 (m, 2H), 1.81-1.72 (m, 2H); LCMS: 302 [M+H].

E6.2. Synthesis ofspiro[naphtho[1,2-b][1,4]oxathiine-2,3′-piperidine]-5,6-dione (Compound17)

Step (i): It was carried out using tert-butyl3-hydroxy-3-(mercaptomethyl)piperidine-1-carboxylate,naphthalene-1,2-dione, tetrahydrofuran as the solvent and conditionsoutlined in procedure F [step (i)]. The intermediate was used in step(ii) without any purification.

Step (ii): Compound 17 was synthesized using conditions as outlined inprocedure F [step (ii)]. M.p.=128-134° C.; 400 MHz ¹H NMR (CDCl₃) δ:8.04 (dd, J=1.2 and 7.6 Hz, 1H), 7.78 (dd, J=0.8 and 7.6 Hz, 1H), 7.65(dt, J=1.2 and 7.6 Hz, 1H), 7.48 (dt, J=1.2 and 7.6 Hz, 1H), 3.18 (d,J=13.2 Hz, 1H), 3.05-2.92 (m, 4H), 2.85-2.79 (m, 1H), 2.18-2.11 (m, 1H),1.88-1.88-1.65 (m, 3H); LCMS: 302 [M+H].

E6.3. Synthesis of9-chlorospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 18)

Step (i): tert-butyl4-{[(7-chloro-3,4-dioxo-3,4-dihydronaphthalen-1-yl)thio]methyl}-4-hydroxypiperidine-1-carboxylatewas synthesized using tert-butyl4-hydroxy-4-(mercaptomethyl)piperidine-1-carboxylate,6-chloronaphthalene-1,2-dione, acetonitrile as the solvent andconditions outlined in procedure F [step(i)]. The intermediate waspurified by flash column chromatography (SiO₂, 30% EtOAc in hexanes to50% EtOAc in hexanes).

Step (ii): Compound 18 was synthesized using conditions as outlined inprocedure F [step (ii)]. M.p.=>300° C.; 400 MHz ¹H NMR (DMSO-d₆) δ:7.91-7.86 (m, 1H), 7.67-7.62 (m, 2H), 3.07 (s, 2H), 2.86-2.77 (m, 4H),1.93-1.89 (m, 2H), 1.71-1.64 (m, 2H); LCMS: 336 [M+H].

E6.4. Synthesis of9-fluorospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 19)

Step (i): tert-butyl4-{[(7-fluoro-3,4-dioxo-3,4-dihydronaphthalen-1-yl)thio]methyl}-4-hydroxypiperidine-1-carboxylatewas synthesized using tert-butyl4-hydroxy-4-(mercaptomethyl)piperidine-1-carboxylate,6-fluoronaphthalene-1,2-dione, acetonitrile as the solvent andconditions outlined in procedure F [step(i)]. The intermediate waspurified by flash column chromatography (SiO₂, 30% EtOAc in hexanes to50% EtOAc in hexanes).

Step (ii): Compound 19 was synthesized using conditions as outlined inprocedure F [step(ii)]. 400 MHz ¹H NMR (CDCl₃) δ: 8.10-8.07 (m, 1H),7.45-7.42 (dd, J=9.39, 2.34 Hz, 1H), 7.17-7.2 (dt, J=16.43, 8.21 Hz,1H), 3.07-3.05 (m, 4H), 2.11-1.76 (m, 6H); LCMS: 320 [M+H]

E6.5. Synthesis of9-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 20)

Step (i): tert-butyl4-hydroxy-4-{[(7-methoxy-3,4-dioxo-3,4-dihydronaphthalen-1-yl)thio]methyl}piperidine-1-carboxylatewas synthesized using tert-butyl4-hydroxy-4-(mercaptomethyl)piperidine-1-carboxylate,6-methoxynaphthalene-1,2-dione, acetonitrile as the solvent andconditions outlined in procedure F [step(i)]. The crude intermediate wasused in step (ii) without any further purification.

Step (ii): Compound 20 was synthesized using conditions as outlined inprocedure F and purified by preparative thin layer chromatography (SiO₂)to afford the desired product as a purple solid (combined yield for twosteps: 0.054 g, 22%). M.p.=224-226° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 7.88(d, J=8.8 Hz, 1H), 7.20 (s, 1H), 7.08 (d, J=8.4 Hz, 1H), 3.89 (s, 3H),3.11 (s, 2H), 2.82 (brs, 4H), 1.88 (m, 2H), 1.65 (m, 2H); LCMS: 332[M+H].

Example 7 Procedure G

E7.1. Synthesis of tert-butyl8-methoxy-5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylate(Compound 21)

Step (i): To a solution of 7-methoxynaphthalene-1,2-dione (3.88 g, 20.3mmol) and tert-butyl4-hydroxy-4-(mercaptomethyl)piperidine-1-carboxylate (5.70 g, 23.1 mmol)in acetonitrile (120 mL) was added potassium carbonate (5.71 g, 41.3mmol). The reaction was stirred at room temperature for 1.5 hours. Thesolvent was removed under reduced pressure and the crude product used instep (ii) without any further purification.

Step (ii): The crude intermediate from step (i) (7.1 g) was dissolved indichloromethane (100 mL) and trifluoroacetic acid (75 mL) was addeddrop-wise over the course of 1 hour. The reaction was stirred at roomtemperature for 24 hours and the solvent removed under reduced pressure.The crude product was dissolved in methanol and dichloromethane (1:9)(40 mL) and washed with water (3×40 mL). The aqueous layers werecombined, neutralized with saturated NaHCO₃, and washed with methanoland dichloromethane (1:9) (4×20 mL). The organic layers were combined,dried over MgSO₄, and the concentrated under reduced pressure to yield apurple solid (2.9 g). This product was carried out on to step (iii)without any further purification.

Step (iii): The crude intermediate from step (ii) (2.88 g, 8.69 mmol)was dissolved in saturated NaHCO₃ (25 mL) and dichloromethane (60 mL).To the stirring solution was then added di-tert-butyl dicarbonate (3.50g, 16.0 mmol) and the reaction was stirred for 15 minutes at roomtemperature. The reaction mixture was poured into a seperatory funneland the layers were allowed to separate. The aqueous layer was washedwith DCM (4×20 mL). The organic extracts were combined, dried overMgSO₄, and concentrated under reduced pressure to yield a purple solid(4.2 g). The crude product was purified by flash column chromatography(SiO₂, 50% EtOAc in hexanes) to afford the product as a purple solid(combined yield for three steps: 3.62 g, 41%). M.p.=231-232° C.; 400 MHz¹H NMR (DMSO-d₆) δ: 7.76 (d, J=7.8 Hz, 1H), 7.37 (d, J=1.2 Hz, 1H), 7.26(dd, J=2.2, 8.0 Hz, 1H), 3.87 (s, 3H), 3.08 (s, 2H), 2.06-1.93 (m, 2H),1.76-1.67 (m, 2H), 1.42 (s, 9H). LCMS: 432 [M+H]

E7.2. Synthesis of tert-butyl9-bromo-5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylate(Compound 22)

Step (i): tert-butyl4-{[(7-bromo-3,4-dioxo-3,4-dihydronaphthalen-1-yl)thio]methyl}-4-hydroxypiperidine-1-carboxylatewas synthesized using 6-bromonaphthalene-1,2-dione, tert-butyl4-hydroxy-4-(mercaptomethyl)piperidine-1-carboxylate, acetonitrile as asolvent and conditions outlined in procedure G [Step (i)].

Step (ii):9-bromospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione wassynthesized using conditions as outlined in procedure G [Step (ii)].

Step (iii): Compound 22 was synthesized using conditions as outlined inprocedure G [Step (iii)]. M.p.=199-201° C.; 400 MHz ¹H NMR (DMSO-d₆) δ:7.84 (d, J=1.2 Hz, 1H), 7.79 (m, 2H), 3.81 (d, J=14 Hz, 2H), 3.20 (br,2H), 3.11 (s, 2H), 2.01 (br, 1H), 1.97 (br, 1H), 1.78-1.70 (m, 2H), 1.42(s, 9H); LCMS: 482 [M+H].

E7.3. Synthesis of tert-butyl5′,6′-dioxo-5′,6′-dihydro-1H-spiro[azepane-4,2′-naphtho[1,2-b][1,4]oxathiine]-1-carboxylate(Compound 23)

Step (i): tert-butyl4-{[(3,4-dioxo-3,4-dihydronaphthalen-1-yl)thio]methyl}-4-hydroxypiperidine-1-carboxylatewas synthesized using 6-naphthalene-1,2-dione, tert-butyl4-hydroxy-4-(mercaptomethyl)azepane-1-carboxylate, tetrahydrofuran as asolvent and conditions outlined in procedure G [Step (i)].

Step (ii): spiro[azepane-4,2′-naphtho[1,2-b][1,4]oxathiine]-5′,6′-dionewas synthesized using conditions as outlined in procedure G [Step (ii)].

Step (iii): Compound 23 was synthesized using conditions as outlined inprocedure G [Step (iii)]. M.p.=62-65° C.; 400 MHz ¹H NMR (CDCl₃) δ: 8.05(dd, J=1.2 and 8 Hz, 1H), 7.73 (dd, J=1.2, 8 Hz, 1H), 7.65 (t, J=8 Hz,1H), 7.49 (t, J=8 Hz, 1H), 3.89-3.32 (m, 4H), 2.99-2.89 (m, 2H),2.30-1.55 (m, 6H), 1.46 (d, J=11.6 Hz, 9H); LCMS: 416 [M+H]

Example 8 General Procedure H

E8.1. Synthesis ofspiro[azepane-4,2′-naphtho[1,2-b][1,4]oxathiine]-5′,6′-dionehydrochloride (Compound 24)

To a solution of tert-butyl5′,6′-dioxo-5′,6′-dihydro-1H-spiro[azepane-4,2′-naphtho[1,2-b][1,4]oxathiine]-1-carboxylate(0.275 g, 0.66 mmol) in dichloromethane (8 ml) was added a 4M solutionof HCl (g) in dioxane (3 ml). The reaction mixture was stirred at roomtemperature for 4 hours followed by addition of diethylether (50 ml).The resulting precipitate was filtered and washed with diethyl ether(3×10 mL) to afford the product as a purple solid (0.2 g, 85%).M.p.=201-205° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 9.11 (brs, 2H), 7.90 (d,J=7.6 Hz, 1H), 7.82-7.75 (m, 2H), 7.58 (t, J=7.2 Hz, 1H), 3.57 (s, 2H),3.34-3.11 (m, 4H), 2.36 (dd, J=7.2 and 15.6 Hz 1H), 2.27-2.21 (m, 2H),2.08-1.98 (m, 2H), 1.90-1.80 (m, 1H); LCMS: 316 [M+H]

E8.2. Synthesis of1′-(piperidin-4-ylcarbonyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dionehydrochloride (Compound 25)

Compound 25 was synthesized using tert-butyl4-[(5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidin]-1′-yl)carbonyl]piperidine-1-carboxylate,ethyl acetate as a solvent instead of dichloromethane and conditionsoutlined in procedure H. M.p.=94-100° C., 400 MHz ¹H NMR (DMSO-d₆) δ9.0-8.86 (br.s, 1H), 8.7-8.5 (br.s, 1H), 7.94-7.88 (m, 1H), 7.88-7.82(m, 1H), 7.78-7.72 (m, 1H), 7.62-7.54 (m, 1H), 4.3-4.2 (m, 1H), 3.98-3.8(m, 1H), 3.55-3.4 (m, 1H), 3.35-3.2 (m, 2H), 3.11 (s, 2H), 3.15-2.84 (m,4H), 2.12-1.97 (m, 2H), 1.85-1.62 (m, 6H); LCMS=413 [M+H].

E8.3. Synthesis of1′-(piperidin-4-ylacetyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dionehydrochloride (Compound 26)

Compound 26 was synthesized using tert-butyl4-[2-(5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidin]-1′-yl)-2-oxoethyl]piperidine-1-carboxylate,ethyl acetate as a solvent instead of dichloromethane and conditionsoutlined in procedure H. M.p.=200-202° C., 400 MHz ¹H NMR DMSO-D₆ δ8.98-8.8 (br. s, 1H), 8.77-8.6 (br. s, 1H), 7.9-7.86 (m, 1H), 7.85-7.8(m, 1H), 7.78-7.65 (m, 1H), 7.6-7.53 (m, 1H), 4.36-4.22 (m, 1H),3.93-3.8 (m, 1H), 3.75-3.35 (m, 4H), 3.28-3.18 (m 2H), 3.11 (s, 2H),3.15-3.0 (m, 1H), 2.96-2.8 (m, 2H), 2.34 (d, J=3.3 Hz, 2H), 2.1-1.92 (m,3H), 1.85-1.6 (m, 3H), 1.43-1.24 (m, 2H); LCMS=427 [M+H].

E8.4. Synthesis of9-morpholin-4-ylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dionebis-hydrochloride (Compound 27)

Compound 27 was synthesized using tert-butyl9-morpholin-4-yl-5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylateand conditions outlined in procedure H. M.p.=>300° C.; 400 MHz ¹H NMR(DMSO-d₆) δ: 7.76 (d, J=8.8 Hz, 1H), 7.20 (s, 1H), 7.08 (dd, J=2 and 8.8Hz, 1H), 3.74 (m, 4H), 3.43 (m, 4H), 3.29 (m, 2H), 3.14 (s, 2H), 2.82(brm, 2H), 1.88 (m, 2H), 1.65 (m, 2H); LCMS: 387 [M+H].

E.8.5. Synthesis of1′-piperidin-4-ylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dionebis-hydrochloride (Compound 28)

Compound 28 was synthesized using tert-butyl4-(5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-yl)piperidine-1-carboxylate,3.0 M HCl gas as a solution in ethylacetate instead of dioxane, ethylacetate as a solvent instead of dichloromethane and conditions outlinedin procedure H. M.p.=214-216° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 11.49 (d,1H), 9.17 (s, 1H), 9.01 (s, 1H), 7.90-7.87 (m, 2H), 7.76-7.72 (m, 1H),7.59-7.55 (m, 1H), 3.62-3.55 (m, 4H), 3.42 (d, 2H), 3.12 (s, 3H),2.90-2.86 (m, 2H), 2.48 (d, 2H), 2.35-2.29 (m, 4H), 2.05-1.97 (m, 2H);LCMS: 385 [M+H].

E.8.6. Synthesis of4-aminospiro[cyclohexane-1,2′-naphtho[1,2-b][1,4]oxathiine]-5′,6′-dionehydrochloride (Compound 29)

Compound 29 was synthesized tert-butyl(5′,6′-dioxo-5′,6′-dihydrospiro[cyclohexane-1,2′naphtho[1,2-b][1,4]oxathiin]-4-yl)carbamateas described in procedure H. M.p.=256-257° C.; 400 MHz ¹H NMR (DMSO-d₆)δ: 8.10 (br, 3H), 7.91 (dd, J=7.6 Hz, 1.2 Hz, 1H), 7.86 (d, J=7.6 Hz,1H), 7.76 (td, J=8.0 Hz, 1.2 Hz, 1H), 7.58 (td, J=7.6 Hz, 0.8 Hz, 1H),3.14 (br, 1H), 3.03 (s, 2H), 2.12 (d, J=12.8 Hz, 2H), 1.96-1.88 (m, 2H),1.83-1.63 (m, 4H); LCMS: 316 [M+H].

Example 9 Procedure I

E9.1. Synthesis of8-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 30)

To a solution of tert-butyl8-methoxy-5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylate(1.11 g, 2.60 mmol) in dichloromethane (80 mL) was added a 4.0M solutionof HCl (g) in dioxane (20 mL, 80 mmol). The reaction was stirred at roomtemperature for 1 hour and the solvent was evaporated under reducedpressure. The residue was dissolved in a mixture of dichloromethane (40mL) and saturated NaHCO₃ (40 mL). The organic layer was separated andthe aqueous layer extracted with dichloromethane (3×20 mL). The organicextracts were combined, dried over MgSO₄, and evaporated under reducedpressure to afford the product as a purple solid (0.728 g, 84%).M.p.=130° C. (dec); 400 MHz ¹H NMR (DMSO-d₆) δ: 7.96-7.82 (m, 1H),7.60-7.12 (m, 2H), 3.87 (s, 3H), 3.12-2.94 (m, 2H), 1.94-1.82 (m, 2H),1.72-1.60 (m, 2H); LCMS: 332 [M+H].

E9.2. Synthesis of9-piperidin-1-ylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 31)

Compound 31 was synthesized using tert-butyl5,6-dioxo-9-piperidin-1-yl-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylateand conditions outlined in procedure 1. M.p.=300° C. (dec); 400 MHz ¹HNMR (DMSO-d) δ: 7.76 (dd, J=2, 9.2 Hz, 1H), 7.17 (s, 1H), 6.95 (d, J=8.4Hz, 1H), 3.51 (brs, 4H), 3.02 (s, 2H), 2.81 (brm, 4H), 1.88 (m, 2H),1.65 (brm, 81-1); LCMS: 385 [M+H].

Example 10 General Procedure J

E10.1. Synthesis of9-bromospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 32)

To a solution of tert-butyl9-bromo-5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylate(0.5 g, 1.03 mmol) in dichloromethane (35 mL) was added trifluoroaceticacid (25 mL). The resulting solution was stirred at room temperature for16 hours. The solvent was removed under reduced pressure and the residuedissolved in dichloromethane (50 mL). To the reaction mixture was thenadded a saturated solution of sodium bicarbonate until the pH was 8. Theorganic layer was separated and the aqueous layer extracted withdichloromethane (3×50 mL). The combined organic extracts were dried oversodium sulfate and concentrated under reduced pressure to afford theproduct as red solid in quantitative yield. M.p.=315-320° C.; 400 MHz ¹HNMR (DMSO-d₆) δ: 7.82 (s, 1H), 7.79 (s, 2H), 3.07 (s, 2H), 2.86-2.77 (m,4H), 1.91 (d, J=13.2 Hz, 2H), 1.71-1.63 (m, 2H); LCMS: 382 [M+H].

E10.2. Synthesis of9-pyridin-4-yispiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 33)

Compound 33 was synthesized using tert-butyl5,6-dioxo-9-pyridin-4-yl-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylateand conditions outlined in procedure J. M.p.=223-228° C.; 400 MHz ¹H NMR(DMSO-d₆) δ 8.75 (d, J=5.2 Hz, 2H), 8.05 (s, 1H), 8.04-7.96 (m, 2H),7.78 (d, J=4.4 Hz, 2H), 3.10 (s, 2H), 2.90-2.84 (m, 4H), 1.98 (d, J=12.8Hz, 2H), 1.75-1.67 (m, 2H); LCMS: 379 [M+H].

E10.3. Synthesis of9-pyridin-3-ylspiro[naptho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 34)

Compound 34 was synthesized using tert-butyl5,6-dioxo-9-pyridin-3-yl-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylateand conditions outlined in procedure J. M.p.=213-215° C.; 400 MHz ¹H NMR(DMSO-d₆) δ: 8.96 (s, 1H), 8.69 (m, 1H), 8.17 (d, J=6.8 Hz, 1H),8.04-7.90 (m, 3H), 7.62-7.57 (m, 1H), 3.09 (s, 2H), 2.85 (m, 4H), 1.96(d, J=13.2 Hz, 2H), 1.74-1.66 (m, 2H); LCMS: 379 [M+H].

E10.4. Synthesis of9-[3-(trifluoromethyl)phenyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 35)

Compound 35 was synthesized using of tert-butyl5,6-dioxo-9-[3-(trifluoromethyl)phenyl]-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylateand conditions outlined in procedure J. M.p.=199-203° C.; 400 MHz ¹H NMR(DMSO-d₆) δ: 8.08-7.95 (m, 5H), 7.89-7.79 (m, 2H), 3.09 (s, 2H),2.86-2.82 (m, 4H), 1.96 (d, J=13.2 Hz, 2H), 1.74-1.65 (m, 2H); LCMS: 446[M+H].

E10.5. Synthesis of9-[4-(trifluoromethyl)phenyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 36)

Compound 36 was synthesized using tert-butyl5,6-dioxo-9-[4-(trifluoromethyl)phenyl]-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylateand conditions outlined in procedure J. M.p.=190-240° C.; 400 MHz ¹H NMR(DMSO-d₆) δ: 8.02-7.90 (m, 7H), 3.12 (s, 2H), 2.99-2.89 (m, 4H), 2.03(d, J=13.6 Hz, 2H), 1.80-1.72 (m, 2H); LCMS: 446 [M+H].

E10.6. Synthesis of9-[2-(trifluoromethyl)phenyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 37)

Compound 37 was synthesized using tert-butyl5,6-dioxo-9-[2-(trifluoromethyl)phenyl]-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylateand conditions outlined in procedure J. M.p.=125-127° C.; 400 MHz ¹H NMR(DMSO-d₆) δ: 7.99 (d, J=8.0 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.81 (dd,J=7.6, 7.6 Hz, 1H), 7.75-7.69 (m, 2H), 7.54 (d, J=8.0 Hz, 1H), 7.50 (d,J=8.0 Hz, 1H), 3.06 (s, 2H), 2.84-2.67 (m, 4H), 1.89 (d, J=13.2 Hz, 2H),1.69-1.60 (m, 2H); LCMS: 446 [M+H].

E10.7. Synthesis of9-phenylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 38)

Compound 38 was synthesized using tert-butyl5,6-dioxo-9-phenyl-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylateand conditions outlined in procedure J. M.p.=83-87° C.; 400 MHz ¹H NMR(DMSO-d₆) δ: 8.00-7.96 (m, 2H), 7.86 (dd, J=1.6, 7.6 Hz, 1H), 7.75 (d,J=7.6 Hz, 2H), 7.59-7.47 (m, 3H), 3.09 (s, 2H), 2.88-2.83 (m, 4H), 1.96(d, J=13.2 Hz, 2H), 1.73-1.60 (m, 2H); LCMS: 378 [M+H].

Example 11 Procedure K E11.1. Synthesis of tert-butyl4-{[(3,4-dioxo-3,4-dihydronaphthalen-1-yl)thio]methyl}-4-hydroxypiperidine-1-carboxylate(Compound 12)

To a solution of 4-chloronaphthalene-1,2-dione (1.0 g, 5.2 mmol) andtert-butyl 4-hydroxy-4-(mercaptomethyl)piperidine-1-carboxylate (1.348g, 5.45 mmol) in acetonitrile (20 mL) was added potassium carbonate(2.16 g, 15.6 mmol). The reaction was stirred at room temperature for 2hours. To the reaction mixture was then added EtOAc (40 mL) and thereaction mixture filtered through celite. The solvent was then removedunder reduced pressure. The crude foamy residue was dissolved in EtOAc(40 mL) and the solvent once again removed under reduced pressure. Tothe crude foamy solid was added EtOAc (7 mL) and the reaction mixturestirred for 10 min. An orange solid separated out. Diethyl ether (20 mL)was then added and the solution was left in the refrigerator to ensurethat most of the product crashed out. The solid was filtered and washedwith diethyl ether to afford the product as an orange solid. The motherliquor was concentrated under reduced pressure and purified by flashcolumn chromatography (SiO₂, 40% EtOAc in hexanes) to recover theproduct (1.66 g, 80%) as an orange solid. M.p.=156-157° C.; 400 MHz ¹HNMR (CDCl₃) δ: 8.2-8.14 (m, 1H), 7.9-7.86 (m, 1H), 7.72-7.66 (m, 1H),7.61-7.55 (m, 1H), 6.50 (s, 1H), 4.05-3.85 (m, 2H), 3.25-3.1 (m, 2H),3.19 (s, 2H), 1.9-1.7 (m, 5H), 1.47 (s, 9H); LCMS: 404 [M+H].

Example 12 Procedure L E12.1 Synthesis ofspiro[naphtha[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (Compound16)

To a solution of 4-chloronapthaquinone (1.0 g, 5.20 mmol) indichloromethane (40 mL) was added tert-butyl4-hydroxy-4-(mercaptomethyl)piperidine-1-carboxylate (1.26 g, 5.20 mmol)followed by Hunig's Base (0.91 mL, 5.20 mmol). The reaction mixture wasstirred at room temperature for 30 min. To it was then addedtrifluoroacetic acid (14 mL) and the reaction mixture stirred at roomtemperature for 20 hours. The reaction mixture was then extracted withwater (3×100 mL). The combined aqueous layers were basified with solidsodium bicarbonate to pH 8 and then extracted with dichloromethane(3×100 mL). The combined organic extracts was washed with brine (2×100mL), dried with sodium sulfate and concentrated under reduced pressure.The resulting solid was dissolved in 50% dichloromethane in EtOAc andconcentrated under reduced pressure to afford the product (0.75 g, 48%)as a purple solid. M.p.=230-236° C.; 400 MHz ¹H NMR (CDCl₃) δ: 8.04 (m,1H), 7.79 (m, 1H), 7.66 (m, 1H), 7.49 (m, 1H), 3.10 (m, 4H), 2.95 (m,2H), 2.13 (m, 2H), 1.83 (m, 2H); LCMS: 302 [M+H].

Example 13 Procedure M 13.1. Synthesis of tert-butyl5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylateand spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 109 and 16)

To a solution of tert-butyl4-{[(3,4-dioxo-3,4-dihydronaphthalen-1-yl)thio]methyl}-4-hydroxypiperidine-1-carboxylate(0.50 g, 1.24 mmol) in dichloromethane (12.5 mL) was added sodium iodate(0.736 g, 3.72 mmol) followed by trifluoroacetic acid (238 μL 3.1 mmol).The reaction mixture was stirred at room temperature for 72 hr. Thereaction mixture was then diluted with dichloromethane (75 mL) andwashed with water (2×50 mL). The combined aqueous layer was thenextracted with dichloromethane (25 mL). The resulting aqueous layerafter dichloromethane extraction contained andspiro[naphtha[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione was storedfor further workup. The combined dichloromethane extracts were washedwith brine (50 mL), dried with sodium sulfate and concentrated underreduced pressure. The crude tert-butyl5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylatewas purified by flash column chromatography (SiO₂, 30% EtOAc in hexanes)to afford the product (0.304 g, 62%) as a purple solid. 400 MHz ¹H NMR(CDCl₃) δ 8.05-8.07 (m, 1H), 7.73-7.75 (m, 1H), 7.64-7.68 (m, 1H),7.48-7.52 (m, 1H), 4.04 (br.s 2H), 3.21-3.29 (m, 2H), 2.94 (s, 2H),2.10-2.13 (m, 2H), 1.72-1.80 (m, 2H), 1.48 (s, 9H); LCMS: 402 [M+H]. Theaqueous layer containingspiro[naphtha[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione wasbasified to pH 8 using sodium bicarbonate and extracted withdichloromethane (2×20 mL). The combined organic extracts were washedwith bring (20 mL), dried with sodium sulfate and concentrated underreduced pressure. The presence ofspiro[naphtha[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (0.034 g,7%) was identified by LCMS: 302 [M+H].

Other embodiments are within the following claims. While severalembodiments have been shown and described, various modifications may bemade without departing from the spirit and scope of the presentinvention.

Example 14 Procedure N

E14.1. Synthesis of1′-(2-furoyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 39)

To a solution ofspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (0.1 g,0.33 mmol) in dichloromethane (3.0 mL) was added 2-furoyl chloride(0.050 g, 0.40 mmol) followed by triethylamine (0.114 mL, 0.79 mmol).The reaction mixture was stirred for 1 h at room temperature. Theorganic layer was separated, washed with water (2.0 mL), dried withsodium sulfate and concentrated under vacuum. The crude product wascrystallized from EtOAc and hexanes to give the desired product as apurple solid (0.08 g, 61%). M.p.=165° C.; 400 MHz ¹H NMR (DMSO-d₆) δ7.89-7.85 (m, 3H), 7.78 (t, 1H), 7.57 (t, 1H), 7.02 (d, J=3.6 Hz, 1H),6.63 (d, J=3.6 Hz, 1H), 4.24 (d, 2H), 3.13 (s, 2H), 2.15 (brs, 2H), 2.08(brs, 2H), 1.95 (m, 2H). LCMS: 396 [M+H].

E14.2. Synthesis of1′-[(3,5-dimethylisoxazol-4-yl)carbonyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 40)

Compound 40 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,3,5-dimethylisoxazole-4-carbonyl chloride and conditions outlined inprocedure N. M.p.=274-275° C.; 300 MHz ¹H NMR (DMSO-d₆) δ 8.08 (d, 1H),7.73 (m, 2H), 7.54 (t, 1H), 3.42 (t, 2H), 2.99 (s, 2H), 2.45 (s, 3H),2.31 (s, 3H), 2.21 (m, 2H), 1.90 (brm 2H), 1.58 (s, 2H); LCMS: 425[M+H].

E14.3. Synthesis of1′-(2,5-dimethyl-3-furoyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 41)

Compound 41 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,2,5-dimethyl-3-furoyl chloride and conditions outlined in procedure N.M.p.=234-235° C.; 300 MHz ¹H NMR (DMSO-d₆) δ 8.15 (d, 1H), 7.81 (d, 1H),7.63 (t, 1H), 7.54 (t, 1H), 5.92 (s, 1H), 3.40 (m, 2H), 3.05 (s, 2H),2.40 (s, 3H), 2.21 (s, 3H), 2.18 (m, 2H), 1.90 (m, 2H), 1.60 (s, 2H);LCMS: 424 [M+H].

E14.4. Synthesis of1′-[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 42)

Compound 42 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,1,3-dimethyl-1H-pyrazole-5-carbonyl chloride and conditions outlined inprocedure N. M.p.=244-245° C.; 300 MHz ¹H NMR (DMSO-d₆) δ 8.07 (d, 1H),7.67 (d, 1H), 7.65 (t, 1H), 7.56 (t, 1H), 6.16 (s, 1H), 3.40 (m, 2H),3.86 (s, 3H), 3.01 (s, 2H), 2.26 (s, 3H), 2.24 (m, 2H), 1.92 (m, 2H),1.62 (m, 2H); LCMS: 424 [M+H].

E14.5. Synthesis of1′-(3-furoyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 43)

Compound 43 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 3-furoylchloride and conditions outlined in procedure N. M.p.=234-235° C.; 300MHz ¹H NMR (DMSO-d₆) δ 8.05 (d, 1H), 7.67 (d, 1H), 7.65 (t, 1H), 7.50(t, 1H), 7.24 (s, 2H), 6.58 (s, 1H), 3.46 (m, 2H), 2.96 (s, 2H), 2.20(m, 2H), 1.92 (m, 2H), 1.58 (brs, 2H); LCMS: 396 [M+H].

E14.6. Synthesis of1′-[4-(1H-pyrazol-1-yl)benzoyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 44)

Compound 44 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,4-(1H-pyrazol-1-yl)benzoyl chloride and conditions outlined in procedureN. M.p.=299-300° C.; 300 MHz ¹H NMR (DMSO-d₆) δ 8.06 (d, 1H), 8.0 (s,1H), 7.64 (m, 4H), 7.65 (t, 1H), 7.50 (m, 3H), 6.52 (s, 1H), 3.42 (m,2H), 2.96 (s, 2H), 2.22 (m, 2H), 1.92 (m 2H), 1.58 (s, 2H); LCMS: 472[M+H].

E14.7. Synthesis of1′-[(1,5-dimethyl-1H-pyrazol-3-yl)carbonyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 45)

Compound 45 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,1,5-dimethyl-1H-pyrazole-3-carbonyl chloride and conditions outlined inprocedure N. M.p.=184-185° C.; 300 MHz ¹H NMR (DMSO-d₆) δ 8.04 (d, 1H),7.80 (m, 1H), 7.65 (m, 1H), 7.46 (m, 1H), 6.42 (s, 1H), 3.80 (s, 3H),3.47 (m, 2H), 2.98 (s, 2H), 2.26 (s, 3H), 2.18 (m, 2H), 1.90 (m 2H),1.62 (brs, 2H); LCMS: 424 [M+H].

E14.8. Synthesis of1′-[3-(dimethylamino)benzoyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 46)

Compound 46 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,3-(dimethylamino)benzoyl chloride and conditions outlined in procedureN. M.p.=170-172° C.; LCMS: 449 [M+H].

E14.9. Synthesis of1′-[(4-chlorophenyl)acetyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 47)

Compound 47 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,(4-chlorophenyl)acetyl chloride and conditions outlined in procedure N.M.p.=120-125° C.; 300 MHz ¹H NMR (DMSO-d₆) δ 7.91 (m, 2H), 7.74 (t, 1H),7.56 (t, 1H), 7.35 (m, 2H), 7.25 (m, 2H), 4.10 (dd, 1H), 3.94 (m, 1H),3.77 (dd, J=3.3 Hz, 2H), 3.57 (s, 2H), 3.09 (s, 2H), 2.05 (m, 2H), 1.67(m, 2H); LCMS: 454 [M+H].

E14.9. Synthesis of1′-[(phenylthio)acetyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 48)

Compound 48 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(phenylthio)acetyl chloride and conditions outlined in procedure N.M.p.=155-157° C.; 300 MHz ¹H NMR (DMSO-d₆) δ 7.89 (m, 2H), 7.76 (t, 1H),7.60 (t, 1H), 7.39 (m, 2H), 7.29 (m, 2H), 7.20 (m, 1H), 4.11 (dd, 2H),4.05 (s, 2H), 3.42 (t, 2H), 3.11 (s, 2H), 2.05 (m, 2H), 1.80 (m, 2H);LCMS: 452 [M+H].

E14.10. Synthesis of1′-(2-iodobenzoyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 49)

Compound 49 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,2-iodobenzoyl chloride and conditions outlined in procedure N.M.p.=165-166° C.; 300 MHz ¹H NMR (DMSO-d₆) δ 7.90 (m, 2H), 7.78 (t, 1H),7.58 (m, 2H), 7.39 (m, 3H), 4.31 (dd, 2H), 3.50 (m, 1H), 3.20 (m, 1H),3.13 (s, 2H), 2.05 (d, 2H), 1.82 (m, 2H); LCMS: 532 [M+H].

E14.11. Synthesis of1′-[chloro(phenyl)acetyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 50)

Compound 50 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,chloro(phenyl)acetyl chloride and conditions outlined in procedure N.M.p.=125-126° C.; 300 MHz ¹H NMR (DMSO-d₆) δ 7.62-7.88 (m, 3H),7.35-7.55 (m, 6H), 6.44 (d, 1H), 4.15 (m, 2H), 3.30 (m, 2H), 3.0-3.13 (2s, 2H), 2.0 (m, 2H), 1.65 (m, 2H); LCMS: 454 [M+H].

E14.12. Synthesis of1′-(1-benzothien-2-ylcarbonyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 51)

Compound 51 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,1-benzothiophene-2-carbonyl chloride and conditions outlined inprocedure N. M.p.=110-112° C.; 300 MHz ¹H NMR (DMSO-d₆) δ 8.20 (m, 1H),7.93 (m, 3H), 7.77 (m, 2H), 7.58 (t, 1H), 7.45 (m, 2H), 4.22 (brm, 2H),3.41 (brm, 2H), 3.15 (s, 2H), 2.17 (m, 2H), 1.88 (m, 2H); LCMS: 462[M+H].

E14.13. Synthesis of methyl(5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-yl)(oxo)acetate(Compound 52)

Compound 52 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, methyloxalyl chloride and conditions outlined in procedure N. M.p.=240-241°C.; 300 MHz ¹H NMR (DMSO-d₆) δ 7.88 (d, J=7.8 Hz, 2H), 7.68 (t, 1H),7.57 (t, 1H), 4.18 (m, 1H), 3.83 (s, 3H), 3.41 (brm, 2H), 3.20 (m, 1H),3.14 (s, 2H), 2.07 (m, 2H), 1.80 (m, 2H); LCMS: 388 [M+H].

E14.14. Synthesis of1′-(3,4-dichlorobenzoyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 53)

Compound 53 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,3,4-dichlorobenzoyl chloride and conditions outlined in procedure N.M.p.=221° C.; 300 MHz ¹H NMR (DMSO-d₆) δ 7.89 (m, 2H), 7.74 (m, 3H),7.58 (t, 1H), 7.46 (d, J=8.1 Hz, 1H), 4.40 (m, 1H), 3.56 (brm, 2H), 3.30(m, 1H), 3.10 (s, 2H), 2.08 (m, 2H), 1.85 (m, 2H); LCMS: 474 [M+H].

E14.15. Synthesis of 1′-[3-(trifluoromethyl)benzoyl]spiro[naphtho1,2-b][1,4]oxathiine-2,4′-piperidine-5,6-dione (Compound 54)

Compound 54 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,3-(trifluoromethyl)benzoyl chloride and conditions outlined in procedureN. M.p.=165-166° C.; 300 MHz ¹H NMR (DMSO-d₆) δ 7.70-7.98 (m, 7H), 7.57(m, 1H), 4.40 (m, 1H), 3.55 (brm, 2H), 3.30 (m, 1H), 3.11 (s, 2H), 2.10(m, 1H), 1.85 (m, 3H); LCMS: 474 [M+H].

E14.16. Synthesis of1′-(3-chlorobenzoyl)spiro[naphtho[1,2-b][4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 55)

Compound 55 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,3-chlorobenzoyl chloride and conditions outlined in procedure N.M.p.=155-158° C.; 300 MHz ¹H NMR (DMSO-d₆) δ 7.89 (m, 2H), 7.69 (t, 1H),7.52 (m, 4H), 7.40 (m, 1H), 4.40 (m, 1H), 3.50 (brm, 2H), 3.24 (m, 1H),3.11 (s, 2H), 2.08 (m, 1H), 1.90 (m, 3H); LCMS: 440 [M+H].

E14.17. Synthesis of1′-(3-nitrobenzoyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 56)

Compound 56 as synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,3-nitrobenzoyl chloride and conditions outlined in procedure N.M.p.=160-162° C.; 300 MHz ¹H NMR (DMSO-d₆) δ 8.30 (m, 2H), 7.92 (m, 3H),7.77 (t, 2H), 760 (m, 1H), 4.40 (m, 1H), 3.52 (brm, 2H), 3.24 (m, 1H),3.12 (s, 2H), 2.08 (m, 1H), 1.90 (m, 3H); LCMS: 451 [M+H].

E14.18. Synthesis of1′-isonicotinoylspiro[naphtho[1,2-b]1,4]oxathiine-2,4′-piperidine-5,6-dione(Compound 57)

Compound 57 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,isonicotinoyl chloride and conditions outlined in procedure N.M.p.=267-269° C.; 400 MHz ¹H NMR (CDCl₃) δ 8.73 (d, J=6 Hz, 2H), 8.08(d, J=8 Hz, 1H), 7.75 (m, 1H), 7.70 (m, 1H), 7.66 (t, 1H), 7.52 (t,J=7.6 Hz, 2H), 4.68 (d, J=12 Hz, 1H), 3.63 (m, 1H), 3.50 (m 1H), 3.37(m, 1H), 2.98 (d, 7.6 Hz, 2H), 2.28 (brm, 1H), 2.14 (brm, 1H), 1.91(brm, 1H), 1.73 (brm, 1H); LCMS: 407 [M+H].

E14.19. Synthesis of1′-[(5-methyl-2-phenyl-2H-1,2,3-triazol-4-yl)carbonyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 58)

Compound 58 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,5-methyl-2-phenyl-2H-1,2,3-triazole-4-carbonyl chloride and conditionsoutlined in procedure N. M.p.=275-280° C.; 300 MHz ¹H NMR (CDCl₃) δ 8.07(d, J=7.5 Hz, 1H), 7.99 (d, J=7.5 Hz, 2H), 7.80 (d, J=7.5 Hz, 1H), 7.68(t, J=8.4 Hz, 1H), 7.48 (m, 3H), 7.37 (m, 1H), 4.65 (m, 2H), 3.67 (t,1H), 3.39 (m 1H), 3.01 (s, 2H), 2.57 (s, 3H), 2.30 (brm, 2H), 1.96 (m,2H); LCMS: 487 [M+H].

E14.20. Synthesis of1′-(pyridin-3-ylcarbonyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 59)

Compound 59 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,nicotinoyl chloride and conditions outlined in procedure N.M.p.=218-220° C.; 300 MHz ¹H NMR (CDCl₃) δ 8.71 (brs, 2H), 8.08 (d,J=7.5 Hz, 1H), 7.77 (m, 3H), 7.53 (t, J=7.5 Hz, 1H), 7.40 (m, 1H), 4.62(m, 1H), 3.78 (m, 1H), 3.42 (m 2H), 2.99 (s, 2H), 2.24 (s, 2H), 1.90 (m,2H); LCMS: 407 [M+H].

E14.21. Synthesis of1′-(3-methylbenzoyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 60)

Compound 60 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,3-methylbenzoyl chloride and conditions outlined in procedure N.M.p.=188-190° C.; 300 MHz ¹H NMR (CDCl₃) δ 8.08 (d, J=7.8 Hz, 1H), 7.77(d, J=6.9 Hz, 1H), 7.68 (m, 1H), 7.51 (m, 1H), 7.25 (m, 4H), 4.60 (m,1H), 3.80 (m, 1H), 3.42 (m 2H), 2.98 (s, 2H), 2.38 (s, 3H), 2.24 (brm,2H), 1.90 (brm, 2H); LCMS: 420 [M+H].

E14.22. Synthesis of1′-[(2E)-3-(2-chlorophenyl)prop-2-enoyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 61)

Compound 61 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,2-chlorocinnamoyl chloride and conditions outlined in procedure N.M.p.=110-115° C.; 300 MHz ¹H NMR (DMSO) δ 8.0-7.75 (m, 5H), 7.6-7.4 (m,3H), 7.4-7.25 (m, 1H), 7.2-7.1 (m, 1H), 4.5-4.35 (m, 1H), 3.45-3.05 (m,5H), 2.25-1.7 (m, 4H); LCMS: 466 [M+H].

E14.23. Synthesis of1-(3-chlorobenzoyl)spiro[azepane-4,2′-naphtho[1,2-b][1,4]oxathiine]-1-5′,6′-dione(Compound 62)

Compound 62 was synthesized usingspiro[azepane-4,2′-naphtho[1,2-b][1,4]oxathiine]-5′,6′-dione,3-chlorobenzoyl chloride and conditions outlined in procedure N.M.p.=98-100° C., 400 MHz ¹H NMR (CDCl₃) δ: 8.08-8.06 (m, 1H), 7.76-7.66(m, 2H), 7.52-7.48 (m, 1H), 7.42-7.21 (m, 4H), 3.87-3.86 (m, 1H),3.67-3.49 (m, 3H), 3.05-2.92 (m, 2H), 2.39-2.17 (m, 4H), 2.04-1.96 (m,1H), 1.89-1.76 (m, 1H); LCMS: 454 [M+H].

E14.24. Synthesis of1′-(3-chlorobenzoyl)-8-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 63)

Compound 63 was synthesized using8-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,3-chlorobenzoyl chloride and conditions outlined in procedure N.M.p.=130° C. (dec); 400 MHz ¹H NMR (DMSO-d) δ: 7.82 (d, J=8.6 Hz, 1H),7.55-7.40 (m, 3H), 7.38 (d, J=7.6 Hz, 2H), 7.34 (d, J=7.4 Hz, 1H), 4.42(bs, 1H), 3.87 (s, 3H), 3.58-3.20 (m, 4H), 3.03 (s, 2H), 2.08-2.02 (m,2H), 1.96-1.88 (m, 2H), 1.86-1.78 (m, 2H); LCMS: 470 [M+H].

E14.25. Synthesis of1′-(3-chlorobenzoyl)-9-phenylspiro[naphtho[1,2-b][1.4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 64)

Compound 64 was synthesized using9-phenylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,3-chlorobenzoyl chloride and conditions outlined in procedure N. Mp.:240-241° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 8.01 (d, J=1.6 Hz, 1H), 7.99(d, J=8.0 Hz, 1H), 7.87 (dd, J=1.6, 7.6 Hz, 1H), 7.83-7.76 (m, 2H),7.60-7.46 (m, 6H), 7.41 (dt, J=1.6, 7.6 Hz, 1H), 4.32 (br, 1H), 3.49(br, 2H), 3.14 (s, 2H), 3.35-3.28 (m, 1H), 2.15 (br, 1H), 2.03 (br, 1H),1.90 (br, 2H); LCMS: 516 [M+H].

E14.26. Synthesis of1′-(3-chlorobenzoyl)-9-pyridin-3-ylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 65)

Compound 65 was synthesized using9-pyridin-3-ylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,3-chlorobenzoyl chloride and conditions outlined in procedure N. Mp.:240-242° C.; 400 MHz ¹H NMR (DMSO-d₆) δ 9.04 (d, J=2.0 Hz, 1H), 8.69(dd, J=1.6, 4.8 Hz, 1H), 8.24 (dt, J=1.6, 8.8 Hz, 1H), 8.05 (d, J=1.6Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.93 (dd, J=1.6, 8.4 Hz, 1H), 7.59 (dd,J=4.8, 8.0 Hz, 1H), 7.55-7.47 (m, 3H), 7.41 (d, J=7.6 Hz, 1H), 4.32 (br,1H), 3.50 (br, 2H), 3.38-3.30 (m, 1H), 3.14 (s, 2H), 2.15 (m, 1H), 2.03(m, 1H), 1.90 (nm 2H); LC MS: 519 [M+H].

E14.27. Synthesis of1′-(3-chlorobenzoyl)-9-pyridin-4-ylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 66)

Compound 66 was synthesized using9-pyridin-4-ylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,3-chlorobenzoyl chloride and conditions outlined in procedure N. Yield:99%. Mp.: 265-267° C.; 400 MHz ¹H NMR (DMSO-d₆) δ 8.75 (m, 2H), 8.08 (d,J=1.6 Hz, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.98 (dd, J=1.6, 8.0 Hz, 1H),7.83 (m, 2H), 7.56-7.47 (m, 3H), 7.41 (dt, J=1.2, 7.6 Hz, 1H), 4.32 (br,1H), 3.50 (br, 2H), 3.38-3.30 (m, 1H), 3.14 (s, 2H), 2.15 (m, 1H), 2.02(m, 1H), 1.91 (m, 2H); LCMS: 517 [M+H].

E14.28. Synthesis of9-chloro-1′-(3-chlorobenzoyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 67)

Compound 67 was synthesized using9-chlorospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,3-chlorobenzoyl chloride and conditions outlined in procedure N. (81 mg,95%); M.p.=125-130° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 7.90 (d, J=8.4 Hz,1H), 7.76 (d, J=1.6 Hz, 1H), 7.63 (dd, J=1.2 and 8.4 Hz, 1H), 7.55-7.48(m, 3H), 7.42 (d, J=7.2 Hz, 1H), 4.4-4.2 (m, 1H), 3.84 (brs, 2H),3:34-3.24 (m, 1H), 3.12 (s, 2H), 2.19-2.08 (m, 1H), 2.02-1.8 (m, 3H);LCMS: 474 [M+H].

E14.29. Synthesis of9-bromo-1′-(3-chlorobenzoyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 68)

Compound 68 was synthesized using9-bromospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,3-chlorobenzoyl chloride and conditions outlined in procedure N.M.p.=135-140° C.; 400 MHz ¹H NMR (CDCl₃) δ: 7.93-7.91 (m, 1H), 7.83-7.82(m, 1H), 7.67-7.64 (m, 1H), 7.45-7.25 (m, 4H), 4.65-4.5 (bs, 1H),3.80-3.65 (bs, 1H), 3.55-3.35 (m, 2H), 2.98 (s, 2H), 2.30-2.05 (m, 2H),2.00-1.67 (m, 2H); LCMS: 518 [M+H].

E14.30. Synthesis of1′-(3-chlorobenzoyl)-9-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 69)

Compound 69 was synthesized using9-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,3-chlorobenzoyl chloride and conditions outlined in procedure N.M.p.=125-127° C.; 400 MHz ¹H NMR (CDCl₃) 8: LCMS: 7.90 (d, 1H),7.55-7.47 (m, 3H), 7.41 (m, 1H), 7.25 (d, 1H), 7.11 (dd, 1H), 3.94, (s,3H), 3.55-3.40 (m, 2H), 3.11 (s, 2H), 2.18-1.92 (m, 4H), 1.89-1.82 (m,2H); LCMS: 470 [M+H].

E14.31. Synthesis ofN-(5′,6′-dioxo-5′,6′-dihydrospiro[cyclohexane-1,2′-naphtho[1,2-b][1,4]oxathiin]-4-yl)-3-(trifluoromethyl)benzamide(Compound 70)

Compound 70 was synthesized using4-aminospiro[cyclohexane-1,2′-naphtho[1,2-b][1,4]oxathiine]-5′,6′-dionehydrochloride, 3-(trifluoromethyl)benzoyl chloride, triethylamine toneutralize the hydrochloride and conditions outlined in procedure N.M.p.=266-267° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 8.66 (d, J=7.8 Hz, 1H),8.21-8.16 (m, 2H), 7.92 (d, J=7.4 Hz, 1H), 7.85 (t, J=7.1 Hz, 1H), 7.80(t, J=7.1 Hz, 1H), 7.74 (t, J=7.1 Hz, 1H), 7.58 (t, J=7.1 Hz, 1H),4.08-3.94 (m, 1H), 3.06 (s, 2H), 2.20-2.10 (m, 2H), 1.94-1.72 (m, 7H),LCMS: 488 [M+H].

Example 15 Procedure O

E15.1. Synthesis of tert-butyl4-[(5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-yl)carbonyl]piperidine-1-carboxylate(Compound 71)

To a solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid(0.628 g, 2.74 mmol) in dimethyl formamide (20 mL) was added HBTU (1.039g, 2.74 mmol), dimethylamino pyridine (0.335 g, 2.74 mmol) followed byspiro[naphtho[1,2-b][1,4]oxathiine-2,4-piperidine]-5,6-dione (0.75 g,2.49 mmol). The reaction mixture was stirred at room temperature for 16hours. To the reaction was added water (100 mL) and the aqueous layerextracted with EtOAc (3×50 mL). The combined organic extract was washedwith 1.0N HCl (2×100 mL), saturated sodium bicarbonate (2×100 mL),saturated sodium chloride (2×100 mL), dried with sodium sulfate andconcentrated under reduced pressure. The crude product was purified byflash column chromatography (SiO₂, 20% EtOAc in dichloromethane) toafford the product as a purple solid (0.81 g, 63%). M.p.=94-100° C.,(DMSO-d₆) δ: 7.93-7.84 (m, 2H), 7.8-7.72 (m, 1H), 7.6-7.52 (m, 1H),4.33-4.22 (m, 1H), 4.0-3.85 (m, 3H), 3.5-3.4 (m, 1H), 3.11 (s, 2H),3.1-3.0 (m, 1H), 2.98-2.7 (m, 31-1), 2.13-1.96 (m, 2H), 1.88-1.58 (m,5H), 1.5-1.4 (m, 1H), 1.4 (s, 9H); LCMS=513 [M+H].

E15.2. Synthesis of tert-butyl4-[2-(5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-yl)-2-oxoethyl]piperidine-1-carboxylate(Compound 72)

Compound 72 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,[1-(tert-butoxycarbonyl)piperidin-4-yl]acetic acid and conditionsoutlined in procedure O. M.p.=110-113° C., (DMSO-d₆) δ:7.94-7.88 (m,1H), 7.87-7.8 (m, 1H), 7.78-7.71 (m, 1H), 7.6-7.52 (m, 1H), 4.36-4.22(m, 1H), 4.0-3.8 (m, 2H), 3.48-3.28 (m, 2H), 3.1 (s, 2H), 3.1-3.0 (m,1H), 2.8-2.6 (m, 2H), 2.29 (d, J=3.6 Hz, 2H), 2.1-1.96 (m, 2H), 1.95-1.6(m, 4H), 1.39 (s, 9H), 1.15-0.98 (m, 2H); LCMS=527 [M+H].

E15.3. Synthesis of1′-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-ylcarbonyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 73)

Compound 73 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinone-1-carboxylic acid conditionsoutlined in procedure O. M.p.=265-267° C.; 400 MHz ¹H NMR (DMSO-d₆) δ:7.92 (dd, J=0.78, 7.4 Hz, 2H), 7.76-7.80 (m, 2H), 7.59 (t, J=7.4 Hz,1H), 7.49 (d, J=8.2 Hz, 1H), 7.05 (t, J=7.8 Hz, 1H), 6.93 (d, J=7.0 Hz,1H), 4.22 (m, 4H), 3.45 (t, J=11.4 Hz, 2H), 3.16 (s, 2H), 2.95 (t, J=5.8Hz, 2H), 2.06-2.16 (m, 4H), 1.87 (m 2H); LCMS=485 [M+H].

E15.4. Synthesis of1′-(1H-benzimidazol-2-ylcarbonyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 74)

Compound 74 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,1H-benzimidazole-2-carboxylic acid and conditions outlined in procedureO. M.p.=266-268° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 13.17 (s, 1H), 7.92 (m,2H), 7.76 (m, 2H), 7.56 (m, 2H), 7.24-7.35 (m, 2H), 5.46 (d, 1H), 4.48(d, 1H), 3.82 (t, 0H), 3.33 (m, 1H), 3.18 (d, 2H), 2.17 (m, 2H),1.85-2.04 (m, 2H); LCMS=446 [M+H].

Example 16 Procedure P

E16.1. Synthesis of1′-(methylsulfonyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 75)

To a mixture ofspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (0.5 g,1.66 mmol) in dichloromethane (50 mL) was added methanesulfonyl chloride(0.129 ml, 1.67 mmol) followed by triethylamine (1.2 ml, 8.61 mmol). Thereaction was stirred at room temperature for 3 h followed by addition ofwater (50 mL). The organic layer was separated, dried with Na₂SO₄ andconcentrated under reduced pressure. The crude product was purified byflash column chromatography (SiO₂, 5% EtOAc in dichloromethane) toafford the product as a purple solid (0.458 g, 72.7%). M.p.=258° C.; 400¹H NMR (CDCl₃) δ: 8.09-8.06 (m, 1H), 7.71-7.64 (m, 2H), 7.54-7.49 (m,1H), 3.84-3.78 (m, 2H), 3.22-3.14 (m, 2H), 2.97 (s, 2H), 2.88 (s, 3H),2.30-2.23 (m, 2H), 2.00-1.90 (m, 2H); LCMS: 380 [M+H]; Calc. forC₁₇H₁₇NO₅S₂ 0.07 CHCl₃: C, 53.15; H, 4.48; N, 3.633; Found C, 52.37; H,4.44; N, 3.44.

E16.2. Synthesis of1′-[(3,4-dichlorophenyl)sulfonyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 76)

Compound 76 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,3,4-dichlorobenzenesulfonyl chloride and conditions outlined inprocedure P. M.p.=275-276° C.; 400 ¹H NMR (DMSO-d₆) δ: 8.00-7.95 (m,2H), 7.86-7.83 (m, 1H), 7.78-7.74 (m, 1H), 7.55-7.49 (m, 1H), 7.45-7.40(m, 1H), 7.15-7.11 (m, 1H), 3.62-3.53 (m, 2H), 3.09 (s, 2H), 2.66-2.57(m, 2H), 2.13-2.03 (m, 2H), 1.94-1.84 (m, 2H) LCMS: 510 [M+H].

E16.3. Synthesis of1′-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 77)

Compound 77 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl chloride and conditionsoutlined in procedure P. M.p.=265-267° C.; 400 MHz ¹H NMR (DMSO-d₆) δ:8.08-8.05 (m, 1H), 7.87-7.84 (m, 1H), 7.61-7.50 (m, 3H), 7.33-7.29 (m,1H), 3.66-3.60 (m, 2H), 3.11 (s, 2H), 3.02-2.95 (m, 2H), 2.12-2.06 (m,2H), 1.95-1.84 (m, 2H); LCMS: 522 [M+H].

E16.4. Synthesis of1′-(2-thienylsulfonyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 78)

Compound 78 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,thiophene-2-sulfonyl chloride and conditions outlined in procedure P.M.p.=245-248° C.; 400 MHz ¹H NMR (CDCl₃) δ: 8.02-8.05 (m, 1H), 7.70-7.67(m, 1H), 7.61-7.59 (m, 1H), 7.48-7.44 (m, 2H), 7.27-7.22 (m, 1H),7.22-7.18 (m, 1H), 3.79-3.72 (m, 2H), 2.94 (s, 2H), 2.91-2.84 (m, 2H),2.26-2.18 (m, 2H), 2.02-1.91 (m, 2H); LCMS: 448 [M+H].

E16.5. Synthesis of1′-[(1-methyl-1H-imidazol-4-yl)sulfonyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 79)

Compound 79 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,1-methyl-1H-imidazole-4-sulfonyl chloride and conditions outlined inprocedure P. M.p.=256-257° C.; 400 MHz ¹H NMR (CDCl₃) δ: 8.06-8.03 (m,1H), 7.64-7.56 (m, 2H), 7.53-7.45 (m, 3H), 3.84-3.78 (m, 5H), 3.30-3.22(m, 2H), 2.93 (s, 2H), 2.22-2.13 (m, 2H), 2.0-1.90 (m, 2H); LCMS: 446[M+H].

E16.6. Synthesis of1′-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 80)

Compound 80 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and conditions outlinedin procedure P. M.p.=273-275° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 7.88-7.85(m, 1H), 7.64-7.58 (m, 1H), 7.56-7.52 (m, 1H), 7.32-7.29 (m, 1H), 3.72(s, 3H), 3.50-3.44 (m, 2H), 3.09 (s, 2H), 2.71-2.65 (m, 2H), 2.38 (s,3H), 2.22 (s, 3H), 2.11-2.05 (m, 2H), 1.91-1.82 (m, 2H); LCMS: 474[M+H].

E16.7. Synthesis of1′-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 81)

Compound 81 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride and conditionsoutlined in procedure P. M.p.=247-249° C.; 400 MHz ¹H NMR (DMSO-d) δ:7.89-7.86 (m, 1H), 7.66-7.61 (m, 1H), 7.57-7.52 (m, 1H), 7.41-7.38 (m,1H), 3.80 (s, 3H), 3.56-3.51 (m, 2H), 3.11 (s, 2H), 2.88-2.81 (m, 2H),2.29 (s, 3H), 2.13-2.06 (m, 2H), 1.93-1.84 (m, 2H); LCMS: 494 [M+H].

E16.8. Synthesis of1′-[(3-chlorophenyl)sulfonyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 82)

Compound 82 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,3-chlorobenzenesulfonyl chloride and conditions outlined in procedure P.M.p.=255-256° C.; 400 ¹H NMR (DMSO-d) δ: 7.98-7.9 (m, 1H), 7.89-7.82 (m,1H), 7.8-7.7 (m, 3H), 7.58-7.4 (m, 2H), 7.3 (d, J=7.6 Hz, 1H), 3.65-3.58(m, 2H), 3.1 (s, 2H), 2.6-2.5 (m, 2H), 2.15-2.05 (m, 2H), 1.95-1.84 (m,2H) LCMS: 476 [M+H].

E16.9. Synthesis ofN,N-dimethyl-5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-sulfonamide(Compound 83)

Compound 83 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,dimethylsulfamoyl chloride and conditions outlined in procedure P.M.p.=215-218° C.; 400 MHz ¹H NMR (DMSO-d₆) δ 7.89-7.91 (dd. J=0.78, 7.4Hz, 1H,), 7.76-7.83 (m, J=1.5, 7.4, 7.4 Hz, 2H), 7.55-7.59 (ddd, J=1.5,7.4, 7.4 Hz, 1H), 3.54 (dt, J=3.5, 12.9 Hz, 2H), 3.18-3.21 (t, 2H), 3.14(s, 2H), 2.78 (s, 6H), 2.06-2.10 (m, 2H), 1.82-1.90 (br m 2H); LCMS: 409[M+H].

Example 17 Procedure Q

E17.1. Synthesis of5,6-dioxo-N-phenyl-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxamide(Compound 84)

To a solution ofspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (0.1 g,0.33 mmol) in dichloromethane (4.0 mL) was added the isocyanatobenzene(0.043 g, 0.37 mmol). The reaction mixture was stirred at roomtemperature for 30 min. The solvent was then removed tinder vacuum. Thecrude product was purified by flash column chromatography (SiO₂, 100%dichloromethane to 10% EtOAc in dichloromethane) to give the desiredproduct as a purple solid (0.085 g, 61%). M.p.=228-230° C.; 400 MHz ¹HNMR (CDCl₃) δ: 8.08 (d, J=6.8 Hz, 1H), 7.8-7.7 (m, 1H) 7.67 (t, J=7.6Hz, 1H), 7.55-7.48 (m, 1H), 7.4-7.27 (m, 4H), 7.1-7.03 (m, 1H), 6.40 (s,1H), 4.1-4.0 (m, 2H), 3.5-3.35 (m, 2H), 2.98 (s, 2H), 2.27-2.0 (m, 2H),1.95 1.8 (m, 2H); LCMS: 421 [M+H].

E17.2. Synthesis ofN-(4-fluorophenyl)-5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxamide(Compound 85)

Compound 85 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,1-fluoro-4-isocyanatobenzene and conditions outlined in procedure Q.M.p.=218-220° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 8.64 (s, 1H), 7.95-7.8 (m,2H), 7.8-7.7 (m, 1H), 7.6-7.5 (m, 1H), 7.5-7.4 (m, 2H), 7.15-7.0 (m,2H), 4.15-4.0 (m, 2H), 3.4-3.2 (m, 2H), 3.13 (s, 2H), 2.1-1.95 (m, 2H),1.9-1.7 (m, 2H); LCMS: 439 [M+H].

E17.3. Synthesis of5,6-dioxo-N-[3-(trifluoromethyl)phenyl]-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxamide(Compound 86)

Compound 86 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,1-isocyanato-3-(trifluoromethyl)benzene and conditions outlined inprocedure Q. M.p.=216-218° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 8.95 (s, 1H),8.0-7.82 (m, 3H), 7.8-7.72 (m, 2H), 7.61-7.54 (m, 1H), 7.5-7.4 (m, 1H),7.28-7.22 (m, 1H), 4.17-4.0 (m, 2H), 3.38-3.22 (m, 2H), 3.14 (s, 2H),2.1-2.0 (m, 2H), 1.9-1.75 (m, 2H); LCMS: 489 [M+H].

E17.4. Synthesis ofN-(3,4-dichlorophenyl)-5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxamide(Compound 87)

Compound 87 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,1,2-dichloro-4-isocyanatobenzene and conditions outlined in procedure Q.M.p.=245-246° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 8.90 (s, 1H), 7.94-7.84(m, 3H), 7.79-7.73 (m, 1H), 7.6-7.55 (m, 1H), 7.52-7.44 (m, 2H), 4.1-4.0(m, 2H), 3.34-3.22 (m, 2H), 3.13 (s, 2H), 2.1-2.0 (m, 2H), 1.86-1.76 (m,2H); LCMS: 489 [M+H].

E17.5. Synthesis ofN-[4-(dimethylamino)phenyl]-5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxamide(Compound 88)

Compound 88 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,4-isocyanato-N,N-dimethylaniline and conditions outlined in procedure Q.M.p.=222-224° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 8.31 (s, 1H), 7.95-7.85(m, 2H), 7.8-7.72 (m, 1H), 7.6-7.55 (m, 1H), 7.27-7.20 (m, 2H), 6.7-6.6(m, 2H), 4.1-3.97 (m, 2H), 3.3-3.18 (m, 2H), 3.13 (s, 2H), 2.82 (s, 6H),2.08-1.98 (m, 2H), 1.85-1.75 (m, 2H); LCMS: 464 [M+H].

E17.6. Synthesis of5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxamide(Compound 89)

Compound 89 was synthesized usingspiro[naphtha[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,isocyanato(trimethyl)silane and conditions outlined in procedure Q.M.p.=218-220° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 7.90 (d, J=6.8 Hz, 1H),7.83 (d, J=8.0 Hz, 1H), 7.75 (t, J=7.6 Hz, 1H), 7.56 (t, J=8.0 Hz, 1H),6.05 (s, 2H), 3.86 (d, J=13.6 Hz, 2H), 3.15-3.10 (m, 4H), 1.95 (d,J=13.6 Hz, 2H), 1.73-1.67 (m, 2H); LCMS: 345 [M+H].

Example 18 Procedure R E18.1. Synthesis of5,6-dioxo-N-pyridin-3-yl-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxamide(Compound 90)

Step (i): To a mixture of nicotinic acid (0.3 g, 2.19 mmol) in toluene(8.0 mL) was added diphenylphosphoryl azide (0.47 mL, 2.19 mmol)followed by triethylamine (0.61 mL, 4.38 mmol). The reaction mixture wasstirred at 90° C. for 2 hours.

Step (ii): The reaction was cooled to room temperature and the resultingsolution of 3-isocyanatopyridine in toluene (3 mL) was then added toanother flask containing a solution ofspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (0.15 g,0.5 mmol) in dichloromethane (5.0 mL). The reaction was stirred at roomtemperature for 30 minutes. The solvent was removed under vacuum. Thecrude product was purified by flash column chromatography (SiO₂, 100%EtOAc to 2% methanol in EtOAc) to give the desired product as a purplesolid (0.182 g, 84%). M.p.=155-160° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 8.81(s, 1H), 8.65 (s, 1H), 8.18-8.13 (m, 1H), 7.95-7.83 (m, 3H), 7.8-7.71(m, 1H), 7.62-7.55 (m, 1H), 7.31-7.24 (m, 1H), 4.15-4.0 (m, 2H), 3.4-3.2(m, 2H), 3.14 (s, 2H), 2.15-2.0 (m, 2H), 1.9-1.76 (m, 2H); LCMS: 422[M+H].

E18.2. Synthesis ofN-(6-methylpyridin-3-yl)-5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxamide(Compound 91)

Compound 91 was synthesized using 6-methylnicotinic acid to synthesize5-isocyanato-2-methylpyridine [Step (i)] followed by [step (ii)] usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione asoutlined in procedure R. M.p.=231-233° C.; 400 MHz ¹H NMR (DMSO-d₆) δ:8.7 (s, 1H), 8.5 (s, 1H), 7.97-7.85 (m, 2H), 7.8-7.72 (m, 2H), 7.6-7.53(m, 1H), 7.16-7.1 (m, 1H), 4.15-4.0 (m, 2H), 3.4-3.2 (m, 2H), 3.14 (s,2H), 2.39 (s, 3H), 2.1-2.0 (m, 2H), 1.9-1.76 (m, 2H); LCMS: 436 [M+H].

Example 19 Procedure S

E19.1. Synthesis of phenyl5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylate(Compound 92)

To a mixture ofspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (0.1 g,0.33 mmol) in ethyl acetate (2.0 mL) and aqueous saturated sodiumbicarbonate (2.0 mL) was added phenyl chloridocarbonate (0.057 g). Thereaction mixture was stirred at room temperature for 5 min. The organiclayer was separated, washed with water (2.0 mL), dried with sodiumsulfate and concentrated under vacuum. The crude product wascrystallized from EtOAc/hexanes to give the desired product as a purplesolid (0.08 g, 57%). M.p.=259-261° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 7.88(t, J=7.2 Hz, 2H), 7.75 (t, J=7.2 Hz, 1H), 7.56 (t, J=7.6 Hz, 1H), 7.38(t, J=7.2 Hz, 2H), 7.21 (t, J=7.2 Hz, 1H), 7.12 (d, J=8 Hz, 2H), 4.04(m, 2H), 3.34 (m, 2H), 3.13 (s, 2H), 2.07 (m, 2H), 1.89 (m, 2H); LCMS:422 [M+H].

E19.2. Synthesis of isobutyl5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylate(Compound 93)

Compound 93 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, isobutylchloridocarbonate, EtOAc as the solvent and conditions outlined inprocedure S. M.p.=154-155° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 7.88 (d, J=8Hz, 1H), 7.83 (d, J=8 Hz, 1H), 7.733 (t, J=7.2 Hz, 1H), 7.55 (t, J=7.2Hz, 1H), 3.92 (d, J=13.6 Hz, 2H), 3.78 (d, J=6.4 Hz, 2H), 3.20 (br. s,2H), 3.08 (s, 2H), 2.0 (d, J=15.4 Hz, 2H), 1.96 (m, 1H), 1.73 (t, J=12Hz, 2H), 0.88 (d, J=6.8 Hz, 6H); LCMS: 402 [M+H].

E19.3. Synthesis of vinyl5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1.2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylate(Compound 94)

Compound 94 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, vinylchloridocarbonate, EtOAc as the solvent and conditions outlined inprocedure S. M.p.=191-193° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 7.85 (m, 2H),7.72 (t, J=7.6 Hz, 1H), 7.55 (t, J=7.2 Hz, 1H), 7.14 (m, 1H), 4.80 (d,J=13.6 Hz, 1H), 4.51 (d, J=5.6 Hz, 1H), 3.95 (m, 2H), 3.26 (m, 2H), 3.08(s, 2H), 2.01 (m, 2H), 1.80 (m, 2H); LCMS: 372 [M+H].

E19.4. Synthesis of 2-ethylhexyl5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylate(Compound 95)

Compound 95 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,2-ethylhexyl chloridocarbonate, EtOAc as the solvent and conditionsoutlined in procedure S. M.p.=92-93° C.; 400 MHz ¹H NMR (DMSO-d₆) δ:7.88 (d, J=6.8 Hz 1H), 7.82 (d, J=7.6 Hz, 1H), 7.73 (t, J=7.6 Hz, 1H),7.54 (t, J=7.6 Hz, 1H), 3.91 (m, 4H), 3.24 (brm, 2H), 3.08 (s, 2H), 2.0(d, J=13.6 Hz, 2H), 1.73 (m, 2H), 1.52 (m, 1H), 1.28 (m, 8H), 0.84 (t,J=7.2 Hz, 6H); LCMS: 458 [M+H].

E19.5. Synthesis of 3-(trifluoromethyl)phenyl5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylate(Compound 96)

Compound 96 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,3-(trifluoromethyl)phenyl chloridocarbonate, EtOAc as the solvent andconditions outlined in procedure S. M.p.=225-226° C.; 400 MHz ¹H NMR(DMSO-d₆) δ: 7.88 (t, J=8.8 Hz, 2H), 7.76 (t, J=7.2 Hz, 1H), 7.55-7.66(m, 3H), 7.48 (d, J=8 Hz, 1H), 7.04 (m, 1H), 4.09 (m, 2H), 3.46 (t,J=12.4, 2H), 3.13 (s, 2H), 2.09 (m, 2H), 1.92 (m, 2H); LCMS: 490 [M+H].

E19.6. Synthesis of 4-fluorophenyl5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylate(Compound 97)

Compound 97 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,4-fluorophenyl chloridocarbonate, EtOAc as the solvent and conditionsoutlined in procedure S. M.p.=212-214° C.; 400 MHz ¹H NMR (DMSO-d₆) δ:7.88 (m, 2H), 7.75 (t, J=8 Hz, 1H), 7.56 (t, J=8 Hz, 1H), 7.15-7.23 (m,4H), 4.10 (m, 2H), 3.40 (m, 2H), 3.13 (s, 2H); 2.09 (m, 2H), 1.90 (m,2H); LCMS: 440 [M+H].

E19.7. Synthesis of benzyl5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylate(Compound 98)

Compound 98 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, benzylchloridocarbonate, EtOAc as the solvent and conditions outlined inprocedure S. M.p.=222-224° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 7.87 (d, J=8Hz, 1H), 7.82 (d, J=8 Hz, 1H), 7.73 (t, J=7.2 Hz, 1H), 7.54 (t, J=7.2Hz, 1H), 7.15-7.30 (m, 5H), 4.23 (d, J=5.6 Hz, 2H), 3.90 (d, J=13.6 Hz,2H), 3.15 (t, J=11.6 Hz, 2H), 3.08 (s, 2H), 1.95 (d, J=12.4, 2H), 1.70(m, 2H); LCMS: 436 [M+H].

E19.8. Synthesis of 3-(trifluoromethyl)phenyl9-bromo-5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylate(Compound 99)

Compound 99 was synthesized using9-bromospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,3-(trifluoromethyl)phenyl chloridocarbonate, EtOAc as the solvent andconditions outlined in procedure S. M.p.=210-211° C.; 400 MHz ¹H NMR(CDCl₃) δ: 7.95-7.92 (m, 1H), 7.85-7.84 (m, 1H), 7.68-7.65 (m, 1H),7.52-7.49 (m, 2H), 7.43-7.41 (m, 1H), 7.36-7.32 (m, 1H), 4.33-4.18 (m,2H), 3.55-3.35 (m, 2H), 3.00 (s, 2H), 2.30-2.20 (m, 2H), 1.95-1.86 (m,2H); LCMS: 568 [M+H].

E19.9. Synthesis of 3-(trifluoromethyl)phenyl9-fluoro-5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylate(Compound 100)

Compound 100 was synthesized using9-fluorospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,3-(trifluoromethyl)phenyl chloridocarbonate, EtOAc as the solvent andconditions outlined in procedure S. M.p.=101-105° C., 400 MHz ¹H NMR(DMSO-d₆) δ: 8.00-7.97 (m, 1H), 7.67-7.57 (m, 4H), 7.51-7.49 (d, J=7.82Hz, 1H), 7.43-7.38 (dt, J=8.21, 16.82 Hz, 1H), 4.11-3.92 (m, 2H),3.54-3.48 (m, 2H), 3.15 (s, 2H), 2.11-1.87 (m, 4H); LCMS: 508 [M+H]

E19.10. Synthesis of 3-(trifluoromethyl)phenyl9-chloro-5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylate(Compound 101)

Compound 101 was synthesized using9-chlorospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,3-(trifluoromethyl)phenyl chloridocarbonate, triethylamine instead ofaqueous sodium bicarbonate, dichloromethane as a solvent and conditionsoutlined in procedure S. M.p.=109-112° C.; 400 MHz ¹H NMR (DMSO-d₆) δ:7.90 (d, J=8 Hz, 1H), 7.77 (d, J=2 Hz, 1H), 7.68-7.59 (m, 4H), 7.50 (d,J=7.6 Hz, 1H), 4.08 (d, J=13.2 Hz, 1H), 3.94 (d, J=12.4 Hz, 1H), 3.51(t, J=11.6 Hz, 1H), 3.39-3.34 (m, 1H), 3.16 (s, 2H), 2.15-2.09 (m, 2H),2.00-1.85 (m, 2H); LCMS: 524 [M+H].

E19.11. Synthesis of 3-(trifluoromethyl)phenyl5′,6′-dioxo-5′,6′-dihydro-1H-spiro[azepane-4,2′-naphtho[1,2-b][1,4]oxathiine]-1-carboxylate(Compound 102)

Compound 102 was synthesized usingspiro[azepane-4,2′-naphtho[1,2-b][1,4]oxathiine]-5′,6′-dione,3-(trifluoromethyl)phenyl chloridocarbonate, triethylamine instead ofaqueous sodium bicarbonate, dichloromethane as a solvent and conditionsoutlined in procedure S. M.p.=111-114° C., 400 MHz ¹H NMR (DMSO-d₆) δ:7.91-7.89 (d, J=7.43 Hz, 1H), 7.83-7.79 (m, 1H), 7.73-7.68 (m, 1H),7.67-7.49 (m, 5H), 3.81-3.52 (m, 4H), 3.28-3.09 (m, 2H), 2.33-1.86 (m,6H); LCMS: 504 [M+H].

E19.12. Synthesis of 3-(trifluoromethyl)phenyl5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,3′-piperidine]-1′-carboxylate(Compound 103)

Compound 103 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,3′-piperidine]-5,6-dione,3-(trifluoromethyl)phenyl chloridocarbonate, triethylamine instead ofaqueous sodium bicarbonate, dichloromethane as a solvent and conditionsoutlined in procedure S. M.p.=95-99° C., 400 MHz ¹H NMR (CDCl₃) δ:8.05-7.99 (m, 1H), 7.74-7.66 (m, 2H), 7.52-7.43 (m, 2H), 7.38-7.33 (m,2H), 6.88-6.87 (m, 1H); LCMS: 490 [M+H].

E19.13. Synthesis of 3-(trifluoromethyl)phenyl8-methoxy-5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylate(Compound 104)

Compound 104 was synthesized using8-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,3-(trifluoromethyl) phenyl chloroformate, triethylamine instead ofaqueous sodium bicarbonate, dichloromethane as a solvent and conditionsoutlined in procedure S. M.p.=233-234° C.; 400 MHz ¹H NMR (DMSO-d₆) δ:7.82 (d, J=8.4 Hz, 1H), 7.62 (m, 3H), 7.50 (brd, J=8 Hz, 1H), 7.38 (d,J=2.8 Hz, 1H), 7.27 (dd, J=2.4 and 8.4 Hz, 1H), 4.11 (m, 1H), 3.99 (m,1H), 3.88 (s, 3H), 3.40 (m, 2H), 3.13 (s, 2H), 2.11 (m, 2H), 1.93 (m,2H); LCMS: 520 [M+H].

E19.14. Synthesis of 3-(trifluoromethyl)phenyl5,6-dioxo-9-phenyl-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylate(Compound 105)

Compound 105 was synthesized using9-phenylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,3-(trifluoromethyl)phenyl chloroformate, triethylamine instead ofaqueous sodium bicarbonate, dichloromethane as a solvent and conditionsoutlined in procedure S. M.p.=188-190° C.; 400 MHz ¹H NMR (DMSO-d₆) δ:8.03 (d, J=1.6 Hz, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.88 (dd, J=1.6, 8.4 Hz,1H), 7.82 (d, J=7.2 Hz, 2H), 7.67-7.55 (m, 5H), 7.50 (dd, J=8.0, 8.0 Hz,2H), 4.10 (br, 1H), 3.97 (br, 1H), 3.56-3.44 (br, 1H), 3.42-3.34 (br,1H), 3.18 (s, 2H), 2.16 (d, J=12.8 Hz, 2H), 2.04-1.88 (m, 2H); LCMS: 566[M+H].

E19.15. Synthesis of 3-(trifluoromethyl)phenyl9-methoxy-5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylate(Compound 106)

Compound 106 was synthesized using9-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,3-(trifluoromethyl)phenyl chloroformate, triethylamine instead ofaqueous sodium bicarbonate, dichloromethane as a solvent and conditionsoutlined in procedure S. M.p.=88-89° C.; 400 MHz ¹H NMR (DMSO-d₆) δ:7.91 (d, J=8.4 Hz, 1H), 7.62 (m, 2H), 7.50 (brd, J=8.0 Hz, 1H), 7.24 (d,J=2.4 Hz, 1H), 7.11 (dd, J=2.4 and 8.4 Hz, 1H), 4.10 (m, 1H), 3.98 (m,1H), 3.94 (s, 3H), 3.45 (m, 2H), 3.15 (s, 2H), 2.10 (m, 2H), 1.95 (m,2H); LCMS: 520 [M+H].

E19.16. Synthesis of 3-(trifluoromethyl)phenyl4-(5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidin]-1′-yl)piperidine-1-carboxylate(Compound 107)

Compound 107 was synthesized using1′-piperidin-4-ylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dionebis hydrochloride, triethylamine instead of aqueous sodium bicarbonate,dichloromethane as a solvent and conditions outlined in procedure S.M.p.=70-73° C.; 400 MHz ¹H NMR (CDCl₃) δ: 8.05-8.03 (m, 1H), 7.51-7.31(m, 1H), 7.67-7.63 (m, 1H), 7.50-7.46 (m, 3H), 7.39 (s, 1H), 7.32-7.29(m, 1H), 4.36 (t, 2H), 3.98-3.89 (m, 1H), 3.63-3.62 (m, 1H), 3.39-3.29(m, 1H), 3.03-2.87 (m, 4H), 2.84-2.58 (m, 2H), 2.18-2.07 (m, 2H),1.95-1.84 (m, 4H), 1.65-1.60 (m, 2H); LCMS: 573 [M+H].

E19.17. Synthesis of 3-(trifluoromethyl)phenyl(5′,6′-dioxo-5′,6′-dihydrospiro[cyclohexane-1,2′-naphtho[1,2-b][1,4]oxathiin]-4-yl)carbamate(Compound 108)

Compound 108 was synthesized using4-aminospiro[cyclohexane-1,2′-naphtho[1,2-b][1,4]oxathiine]-5′,6′-dionehydrochloride, 3-(trifluoromethyl)phenyl chloroformate, triethyl amineto neutralize the hydrochloride and conditions outlined in procedure S.M.p.=198-199° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 8.08 (d, J=7.8 Hz, 1H),7.92 (d, J=7.4 Hz, 1H), 7.83 (t, J=7.1 Hz, 1H), 7.78 (t, J=7.1 Hz, 1H),7.66-7.43 (m, 4H), 3.56-3.47 (m, 1H), 3.04 (s, 2H), 2.16-2.05 (m, 2H),1.94-1.80 (m, 2H), 1.78-1.66 (m, 7H), LCMS: 504 [M+H].

Example 20 Procedure T E20.1. Synthesis of tert-butyl5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylate(Compound 109)

To a mixture ofspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (10.0 g,3.32 mmol) and di-tert-butyl dicarbonate (7.25 g, 3.32 mmol) in THF (150ml) was added 100 ml H₂O and 50 ml concentrated aqueous K₂CO₃. Thereaction was stirred at room temperature for 1 hour. The mixture waspoured onto H₂O (250 mL) and extracted with ethyl acetate (3×250 ml).The organic extract was combined, dried with Na₂SO₄ and concentratedunder reduced pressure. The crude product was purified by flash columnchromatography (SiO₂, 30% EtOAc in hexanes to 50% EtOAc in hexanes) toafford the product as a purple solid. The solid was then recrystallizedfrom EtOAc and hexanes to give the product as purple crystals (3.26 g,24%). 400 MHz ¹H NMR (CDCl₃) δ: 8.08-8.05 (m, 1H), 7.76-7.73 (m, 1H),7.68-7.65 (m, 1H), 7.52-7.49 (m, 1H), 4.08-3.95 (m, 2H), 3.29-3.21 (m,2H), 2.94 (s, 2H), 2.14-2.09 (m, 2H), 1.80-1.70 (m, 2H), 1.48 (s, 9H);LCMS: 402.

Example 21 Procedure U E21.1. Synthesis of pyridin-3-yl5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylate(Compound 110)

Step (i): To a 1.93M solution of phosgene in toluene (20%) (9.92 ml,19.1 mmol) was added anhydrous dichloromethane (5 mL). The mixture wasstirred at 0° C. under an argon atmosphere. A solution of pyridin-3-ol(0.364 g, 3.83 mmol) in anhydrous pyridine (0.413 ml, 5.1 mmol) andanhydrous dichloromethane (10 ml) was added drop-wise to the stirredphosgene solution at 0° C. over a period of 15 minutes. The mixture wasthen allowed to warm to room temperature and stirred for an additional 4h. A stream of nitrogen was passed through the solution to remove thephosgene and solvents. The product was suspended in EtOAc (40 mL) andused as a stock solution in step (ii) without any further purification.

Step (ii): To a solution ofspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (0.5 g,1.66 mmol) in EtOAc (10 mL) was added pyridin-3-yl chloridocarbonate (40ml of a stock solution) in 100 ml EtOAc was added 2M aqueous sodiumcarbonate (200 ml). The reaction mixture was stirred for three hours atroom temperature. The organics layer was separated, washed with water(1×100 ml), dried with sodium sulfate and concentrated under reducedpressure. The crude product was purified by flash column chromatography(SiO₂, 10% EtOAc in dichloromethane to 40% EtOAc in dichloromethane) toafford the product as a purple solid (0.246 g, 33%). M.p.=246-247° C.;400 MHz ¹H NMR (DMSO-d₆) δ: 8.31-8.34 (m, 1H), 7.91-7.86 (m, 3H),7.77-7.71 (m, 1H), 7.52-7.58 (m, 1H), 7.29-7.33 (m, 1H), 7.16-7.18 (m,1H), 4.15-4.22 (m, 1H), 3.93-4.02 (m, 1H), 3.42-3.51 (m, 1H), 3.26-3.38(m, 1H), 3.12-3.16 (m, 2H), 2.05-2.13 (m, 2H), 1.82-1.96 (m, 2H); LCMS:423 [M+H].

E21.2. Synthesis of 6-methyllpyridin-3-yl5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylate(Compound 111)

Step (i): 6-Methylpyridin-3-yl chloridocarbonate was synthesized using6-methylpyridin-3-ol and conditions outlined in procedure U [Step (i)].The product was used in step (ii) without any further purification.

Step (ii): Compound 111 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,6-methylpyridin-3-yl chloridocarbonate and conditions outlined inprocedure U [step (ii)]. M.p.=220-222° C.; 400 MHz ¹H NMR (DMSO-d₆) δ:8.25-8.27 (m, 1H), 7.85-7.91 (m, 2H), 7.72-7.78 (m, 1H), 7.53-7.59 (m,1H), 7.46-7.51 (m, 1H), 7.26-7.30 (m, 1H), 4.07-4.16 (m, 1H), 3.92-3.95(m, 1H), 3.40-3.50 (m, 1H), 3.25-3.36 (m, 1H), 3.13 (s, 2H), 2.44 (s,3H), 2.05-2.15 (m, 2H), 1.80-1.98 (m, 2H); LCMS: 437 [M+H].

E21.3. Synthesis of pyridin-2-yl5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylate(Compound 112)

Step (i): Pyridin-2-yl chloridocarbonate was synthesized usingpyridin-2-ol and conditions outlined in procedure U [step(i)]. Theproduct was used in step (ii) without any further purification.

Step (ii): Compound 112 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,pyridin-2-yl chloridocarbonate and conditions outlined in procedure U[step (ii)]. M.p.=203-205° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 8.41-8.44 (m,1H), 7.86-7.91 (m, 3H), 7.73-7.78 (m, 1H), 7.61-7.65 (m, 1H), 7.54-7.59(m, 1H), 7.43-7.47 (m, 1H), 4.08-4.16 (m, 1H), 3.93-4.02 (m, 1H),3.40-3.52 (m, 1H), 3.26-3.38 (m, 1H), 3.13 (s, 2H), 2.04-2.13 (m, 2H),1.82-1.98 (m, 2H); LCMS: 423 [M+H].

E21.4. Synthesis of pyrrolidin-3-yl5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylatehydrochloride (Compound 113)

Step (i): tert-Butyl 3-[(chlorocarbonyl)oxy]pyrrolidine-1-carboxylatewas synthesized using tert-butyl 3-hydroxypyrrolidine-1-carboxylate andconditions outlined in procedure U [step(i)]. The product was used instep (ii) without any further purification.

Step (ii): 1-(tert-Butoxycarbonyl)pyrrolidin-3-yl5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylatewas synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,tert-butyl 3-[(chlorocarbonyl)oxy]pyrrolidine-1-carboxylate andconditions outlined in procedure U [step (ii)].

Step (iii): Compound 113 was synthesized using1-(tert-butoxycarbonyl)pyrrolidin-3-yl5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylateand conditions outlined in procedure H. M.p.=90-100° C.; 400 MHz ¹H NMR(DMSO-d₆) δ: 9.22-9.0 (br.s, 2H), 7.92-7.89 (m, 1H), 7.85-7.83 (m, 1H),7.78-7.73 (m, 1H), 7.59-7.55 (m, 1H), 5.33 (d, J=3.2 Hz, 2H), 5.22 (m,1H), 4.38 (m, 2H), 3.94 (m, 2H), 3.2 (m, 2H), 3.11 (m, 2H), 3.00 (m,2H), 2.01 (m, 2H), 1.86 (m, 2H); LCMS: 415 [M+H].

E21.5. Synthesis of 3-(dimethylamino)phenyl5,6-dioxo-5,6-dihydro-1′H-spiro-[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylate(Compound 114)

Step (i): 3-(Dimethylamino)phenyl chloridocarbonate was synthesizedusing 3-(dimethylamino)phenol and conditions outlined in procedure U[step(i)]. The product was used in step (ii) without any furtherpurification.

Step (ii): The compound 114 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,3-(dimethylamino)phenyl chloridocarbonate and conditions outlined inprocedure U [step (ii)]. M.p.=244-246° C.; 400 MHz ¹H NMR (DMSO-d₆) δ:7.90-7.89 (m, 2H), 7.80-7.75 (m, 1H), 7.60-7.57 (m, 1H), 7.18-7.14 (m,1H), 6.58-6.55 (m, 1H), 6.43-6.38 (m, 2H), 4.09-3.99 (m, 2H), 3.45-3.30(m, 2H), 3.15 (s, 2H), 2.89 (s, 6H), 2.07-2.11 (m, 2H), 1.90 (brs, 2H);LCMS: 465 [M+H].

E21.6. Synthesis of piperidin-3-yl5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylatehydrochloride (Compound 115)

Step (i): tert-Butyl 3-[(chlorocarbonyl)oxy]piperidine-1-carboxylate wassynthesized using tert-butyl 3-hydroxypiperidine-1-carboxylate andconditions outlined in procedure U [step(i)]. The crude product was usedin step (ii) without any further purification.

Step (ii): 1-(tert-Butoxycarbonyl)piperidin-3-yl5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylatewas synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,tert-butyl 3-[(chlorocarbonyl)oxy]piperidine-1-carboxylate andconditions outlined in procedure U [step (ii)].

Step (iii): Compound 115 was synthesized using1-(tert-butoxycarbonyl)piperidin-3-yl5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylateand conditions outlined in procedure H. M.p.=194-198° C.; 400 MHz ¹H NMR(DMSO-d₆) δ: 9.20 (br.s 1H), 8.75 (br.s 1H), 7.92-7.90 (m, 1H), 7.83 (m,1H), 7.78-7.74 (m, 1H), 7.60-7.56 (m, 1H), 4.90 (br.s, 1H), 4.14 (m,1H), 3.91 (m, 1H), 3.30-3.07 (m, 7H), 2.98 (m, 1H), 2.04-2.01 (m, 2H),1.83-1.66 (m, 6H); LCMS: 429 [M+H].

Example 22 Procedure V

E22.1. Synthesis of1′-[4-(1H-pyrazol-4-yl)benzyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 116)

To a mixture ofspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (0.15 g,0.5 mmol) in anhydrous acetonitrile (5.0 mL) was added4-[4-(bromomethyl)phenyl]-1H-pyrazole (0.24 g, 1.0 mmol) followed bypotassium carbonate (0.20 g, 1.5 mmol). The reaction mixture was stirredat 70° C. for 16 h. The reaction mixture was filtered to remove all thesolids and the solvent removed under vacuum. The crude product waspurified by reverse phase HPLC to give the desired product as a purplesolid (0.005 g, 2.3%). M.p.=190-192° C.; 400 MHz ¹H NMR (CDCl₃) δ: 8.1(d, 1H), 7.9 (s, 1H), 7.8 (d, 1H), 7.6-7.7 (m, 4H), 7.5 (t, 1H), 7.4 (d,2H), 6.5 (s, 1H), 3.6 (s, 2h), 2.9 (s, 2h), 2.8 (d, 2H), 2.5 (t, 2H),2.1 (d, 2H), 1.9 (t, 2H); LCMS: 458 [M+H].

E22.2. Synthesis of1′-(tetrahydrofuran-2-ylmethyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 117)

Compound 117 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,2-(bromomethyl)tetrahydrofuran and conditions outlined in procedure V.M.p.=155-159° C.; 400 MHz ¹H NMR (CDCl₃) δ: 8.05 (d, 1H), 7.75 (d, 1H),7.65 (t, 1H), 7.5 (t, 1H), 4.1 (m, 1H), 3.9 (m, 1H), 3.75 (m, 1H),3.0-2.8 (m, 4H), 2.6-2.4 (m, 4H), 2.2-2.1 (m, 2H), 2.1-1.8 (m, 5H), 1.5(m, 1H); LCMS: 386 [M+H].

E22.3. Synthesis of1′-(2-fluorobenzyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 118)

Compound 118 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,1-(bromomethyl)-2-fluorobenzene and conditions outlined in procedure V.M.p.=118-122° C.; 400 MHz ¹H NMR (CDCl₃) δ: 8.05 (d, 1H), 7.65 (m, 2H),7.5 (t, 1H), 7.4 (t, 1H), 7.3 (m, 1H), 7.15 (t, 1H), 7.05 (t, 1H), 3.7(s, 2H), 2.9 (s, 2H), 2.8 (d, 2H), 2.55 (t, 2H), 2.1 (d, 2H), 1.9 (t,2H); LCMS: 410 [M+H].

E22.4. Synthesis of1′-(tetrahydro-2H-pyran-2-ylmethyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 119)

Compound 119 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,2-(bromomethyl)tetrahydro-2H-pyran and conditions outlined in procedureV. M.p.=135-137° C.; 400 MHz ¹H NMR (CDCl₃) δ: 8.05 (d, 1H), 7.8 (d,1H), 7.65 (t, 1H), 7.5 (t, 1H), 4.0 (d, 1H), 3.5 (dt, 2H), 2.9 (m, 3H),2.65-2.3 (m, 4H), 2.1 (m, 2H), 1.9 (m, 3H), 1.5 (m, 4H), 1.3 (m, 2H);LCMS: 400 [M+H].

E22.5. Synthesis of1′-(4-methylbenzyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 120)

Compound 120 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,1-(bromomethyl)-4-methylbenzene and conditions outlined in procedure V.M.p.=156-158° C.; 400 MHz ¹H NMR (CDCl₃) δ: 8.05 (d, 1H), 7.75 (d, 1H),7.65 (t, 1H), 7.5 (t, 1H), 7.2 (dd, 4H), 3.55 (s, 2H), 2.9 (s, 2H), 2.75(d, 2H), 2.5 (t, 2H), 2.35 (s, 3H), 2.1 (d, 2H), 1.85 (t, 2H); LCMS: 406[M+H].

E22.6. Synthesis of1′-(3-methoxybenzyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]5,6-dione(Compound 121)

Compound 121 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,1-(bromomethyl)-3-methoxybenzene and conditions outlined in procedure V.M.p.=129-131° C.; 400 MHz ¹H NMR (CDCl₃) δ: 8.05 (d, 1H), 7.75 (d, 1H),7.65 (t, 1H), 7.5 (t, 1H), 7.25 (m, 2H), 6.9 (s, 1H), 6.8 (d, 1H), 3.8(s, 3H), 3.55 (s, 2H), 2.9 (s, 2H), 2.75 (d, 2H), 2.5 (t, 2H), 2.1 (d,2H), 1.9 (t, 2H); LCMS: 422 [M+H].

E22.7. Synthesis of1′-(cyclopropylmethyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 122)

Compound 122 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,(bromomethyl)cyclopropane and conditions outlined in procedure V.M.p.=161-164° C.; 400 MHz ¹H NMR (CDCl₃) δ: 8.05 (d, 1H), 7.75 (d, 1H),7.65 (t, 1H), 7.5 (t, 1H), 2.95 (m, 4H), 2.5 (t, 2H), 2.35 (d, 2H), 2.15(d, 2H), 1.9 (t, 2H), 0.9 (s, 1H), 0.55 (d, 2H), 0.15 (s, 2H); LCMS: 356[M+H].

E22.8. Synthesis of4-[(5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidin]-1′-yl)methyl]benzonitrile(Compound 123)

Compound 123 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,4-(bromomethyl)benzonitrile and conditions outlined in procedure V.M.p.=207-211° C.; 400 MHz ¹H NMR (CDCl₃) δ: 8.05 (d, 1H), 7.75 (d, 1H),7.65-7.6 (m, 3H), 7.55-7.45 (m, 3H), 3.6 (s, 2H), 2.9 (s, 2H), 2.7 (m,2H), 2.5 (t, 2H), 2.15 (d, 2H), 1.9 (t, 2H); LCMS: 417 [M+H].

E22.9. Synthesis of1′-(2,4-difluorobenzyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 124)

Compound 124 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,1-(bromomethyl)-2,4-difluorobenzene and conditions outlined in procedureV. M.p.=104-107° C.; 400 MHz ¹H NMR (CDCl₃) δ: 8.05 (d, 1H), 7.65 (m,2H), 7.5 (t, 1H), 7.35 (q, 1H), 6.85 (m, 2H), 3.65 (s, 2H), 2.9 (s, 2H),2.8 (d, 2H), 2.5 (t, 2H), 2.15 (d, 2H), 1.85 (t, 2H); LCMS: 428 [M+H].

E22.10. Synthesis of1′-(4-fluorobenzyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 125)

Compound 125 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,1-(bromomethyl)-2,4-difluorobenzene and conditions outlined in procedureV. M.p.=104-106° C.; 400 MHz ¹H NMR (CDCl₃) δ 8.05 (d, 1H), 7.75 (d,1H), 7.65 (t, 1H), 7.5 (t, 1H), 7.3 (m, 2H), 7.0 (t, 2H), 3.55 (s, 2H),2.9 (s, 2H), 2.75 (d, 2H), 2.45 (t, 2H), 2.1 (d, 2H), 1.85 (t, 2H);LCMS: 410 [M+H].

E22.11. Synthesis of1′-isobutylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 126)

Compound 126 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,1-bromo-2-methylpropane and conditions outlined in procedure V.M.p.=158-161° C.; 400 MHz ¹H NMR (CDCl₃) δ 8.05 (d, 1H), 7.75 (d, 1H),7.65 (t, 1H), 7.5 (t, 1H), 2.9 (s, 2H), 2.75 (d, 2H), 2.4 (t, 2H), 2.15(d, 2H), 2.1 (d, 2H), 1.75-1.9 (m, 3H), 0.9 (s, 6H); LCMS: 358 [M+H].

E22.12. Synthesis of1′-(1-methylbutyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 127)

Compound 127 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,2-bromopentane and conditions outlined in procedure V. M.p.=109-111° C.;400 MHz ¹H NMR (CDCl₃) δ 8.05 (d, 1H), 7.75 (d, 1H), 7.65 (t, 1H), 7.5(t, 1H), 2.9 (s, 2H), 2.8-2.6 (m, 5H), 2.1 (d, 2H), 1.85 (q, 2H), 1.55(m, 1H), 1.4-1.15 (m, 3H), 1.0 (t, 3H), 0.9 (t, 3H); LCMS: 372 [M+H].

E22.13. Synthesis of1′-decylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 128)

Compound 128 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,1-bromodecane and conditions outlined in procedure V. M.p.=110-111° C.;400 MHz ¹H NMR (CDCl₃) δ 8.06 (d, J=1.2 Hz, 1H), 7.8-7.75 (m, 1H),7.75-7.6 (m, 1H), 7.53-7.43 (m, 1H), 2.93 (s, 2H) 2.85-2.75 (m, 2H),2.5-2.35 (m, 4H), 2.2-2.05 (m, 2H), 1.95-1.8 (m, 2H), 1.6-1.43 (m, 2H),1.4-1.18 (m, 14H), 0.9-0.8 (m, 3H); LCMS: 442 [M+H].

E22.14. Synthesis of1′-(2-chloro-6-fluorobenzyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 129)

Compound 129 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,2-(bromomethyl)-1-chloro-3-fluorobenzene and conditions outlined inprocedure V. M.p.=90-92° C.; 300 MHz ¹H NMR (CDCl₃) δ 8.08-8.02 (m, 1H),7.76-7.72 (m, 1H), 7.69-7.62 (m, 1H), 7.52-7.44 (m, 1H), 7.28-7.2 (m,2H), 7.06-6.97 (m, 1H), 3.78 (d, J=2.1 Hz, 2H), 2.91 (s, 2H), 2.9-2.8(m, 2H), 2.7-2.58 (m, 2H), 2.16-2.04 (m, 2H), 1.92-1.78 (m, 2H); LCMS:444 [M+H].

E22.15. Synthesis of1′-benzylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 130)

Compound 130 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,(bromomethyl)benzene and conditions outlined in procedure V.M.p.=170-172° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 7.9 (d, 1H), 7.8-7.7 (m,2H), 7.55 (t, 1H), 7.35-7.2 (m, 5H), 3.55 (s, 2H), 3.05 (s, 2H), 2.7 (d,2H), 2.35 (t, 2H), 1.95 (d, 2H), 1.8 (t, 2H); LCMS: 392 [M+H].

E22.16. Synthesis of1′-allylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 131)

Compound 131 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,3-bromoprop-1-ene and conditions outlined in procedure V. M.p.=166-168°C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 7.9 (d, 1H), 7.75 (s, 2H), 7.55 (s, 1H),5.8 (m, 1H), 5.2-5.1 (m, 2H), 3.1 (s, 2H), 3.0 (d, 2H), 2.7 (d, 2H), 2.3(t, 2H), 1.95 (d, 2H), 1.8 (t, 2H); LCMS: 328 [M+H].

E22.17. Synthesis of1′-(3-methylbutyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 132)

Compound 132 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,3-(bromomethyl)pentane and conditions outlined in procedure V.M.p.=143-146° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 7.9 (d, 1H), 7.75 (d, 2H),7.55 (m, 1H), 3.05 (s, 2H), 2.7 (d, 2H), 2.35-2.2 (m, 4H), 1.95 (d, 2H),1.8-1.7 (d, 2H), 1.6-1.5 (m, 1H), 1.35-1.25 (m, 2H), 0.9-0.8 (m, 6H):LCMS: 372 [M+H].

E22.18. Synthesis of1′-(3-methylbenzyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 133)

Compound 133 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,1-(bromomethyl)-3-methylbenzene and conditions outlined in procedure V.LCMS: 406 [M+H]; R_(t)=1.02 min.

E22.19. Synthesis of2-(5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidin]-1′-yl)-N-phenylpropanamide(Compound 134)

Compound 134 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,2-bromo-N-phenylpropanamide and conditions outlined in procedure V.LCMS: 449 [M+H]; R_(t)=0.98 min.

E22.20. Synthesis of1′-cyclohex-2-en-1-ylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 135)

Compound 135 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,3-bromocyclohexene and conditions outlined in procedure V. LCMS: 382[M+H]; R_(t)=0.94 min.

E22.21. Synthesis of1′-(cyclohexylmethyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 136)

Compound 136 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,(bromomethyl)cyclohexane and conditions outlined in procedure V. LCMS:398 [M+H]; R_(t)=1.03 min.

E22.22. Synthesis of1′-(1-phenylethyl)spiro[naphtho[12-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 137)

Compound 137 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,(1-bromoethyl)benzene and conditions outlined in procedure V. LCMS: 406[M+H]; R_(t)=0.96 min.

E22.23. Synthesis of1′-cyclopentylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 138)

Compound 138 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,bromocyclopentane and conditions outlined in procedure V. LCMS: 370[M+H]; R_(t)=0.90 min.

E22.24. Synthesis of1′-[(2E)-3-phenylprop-2-en-1-yl]spiro[naphtho[1.2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 139)

Compound 139 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,[(1E)-3-bromoprop-1-en-1-yl]benzene and conditions outlined in procedureV. LCMS: 418 [M+H]; R_(t)=1.05 min.

E22.25. Synthesis of1′-(2-phenoxyethyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 140)

Compound 140 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,(2-bromoethoxy)benzene and conditions outlined in procedure V. LCMS: 422[M+H]; R_(t)=1.01 min.

E22.26. Synthesis of1′-(4,4,4-trifluorobutyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 141)

Compound 141 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,4-bromo-1,1,1-trifluorobutane and conditions outlined in procedure V.LCMS: 412 [M+H]; R_(t)=0.96 min.

E22.27. Synthesis of1′-(3-chloro-4-fluorobenzyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 142)

Compound 142 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,4-(bromomethyl)-2-chloro-1-fluorobenzene and conditions outlined inprocedure V. LCMS: 444 [M+H]; R_(t)=1.04 min.

E22.28. Synthesis of1′-but-3-en-1-ylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 143)

Compound 143 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,4-bromobut-1-ene and conditions outlined in procedure V. LCMS: 356[M+H]; R_(t)=0.88 min.

E.22.29. Synthesis of1′-(3-phenoxypropyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 144)

Compound 144 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,(3-bromopropoxy)benzene and conditions outlined in procedure V. LCMS:436 [M+H]; R_(t)=1.05 min.

E22.30. Synthesis of1′-[2-(4-chlorophenoxy)ethyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 145)

Compound 145 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,1-(2-bromoethoxy)-4-chlorobenzene and conditions outlined in procedureV. LCMS: 456 [M+H]; R_(t)=1.07 min.

E22.31. Synthesis of1′-(3-fluoro-4-methylbenzyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 146)

Compound 146 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,4-(bromomethyl)-2-fluoro-1-methylbenzene and conditions outlined inprocedure V. LCMS: 424 [M+H]; R_(t)=1.03 min.

E22.32. Synthesis of1′-(4-fluorobenzyl)-9-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 147)

Compound 147 was synthesized using9-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,1-(bromomethyl)-4-fluorobenzene and conditions outlined in procedure V.M.p.=196-197° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 7.86 (d, J=8.4 Hz, 1H),7.32 (m, 2H), 7.11 (m, 4H), 3.89 (brs, 3H), 3.52 (brs, 2H), 3.04 (s,2H), 2.68 (brd, J=10.8 Hz, 2H), 2.30 (t, J=11.2 Hz, 2H), 1.97 (m, 2H),1.77 (m, 2H); LCMS: 440 [M+H].

E22.33. Synthesis of1′-(4-fluorobenzyl)-9-phenylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 148)

Compound 148 was synthesized using9-phenylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dioneand 1-(bromomethyl)-4-fluorobenzene and conditions outlined in procedureV. M.p.=197-198° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 7.95 (m, 2H), 7.87 (d,J=7.6 Hz, 1H), 7.74 (d, J=6.8 Hz, 2H), 7.60 (m, 2H), 7.52 (m, 1H), 7.34(m, 2H), 7.10 (t, J=8 Hz, m, 2H), 3.5 (s, 2H), 3.10 (s, 2H), 2.71 (m,2H), 2.39 (m, 2H), 2.03 (m, 2H), 1.84 (m, 2H); LCMS: 486 [M+H].

E22.34. Synthesis of1′-(4-phenylbutyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 149)

Compound 149 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione and(4-bromobutyl)benzene and conditions outlined in procedure V.M.p.=145-147° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 7.93-7.88 (m, 1H),7.84-7.73 (m, 2H), 7.62-7.52 (m, 1H), 7.35-7.1 (m, 5H), 3.06 (s, 2H),2.76-2.64 (m, 2H), 2.62-2.54 (m, 2H), 2.4-2.2 (m, 4H), 2.04-1.9 (m, 2H),1.87-1.7 (m, 2H), 1.68-1.4 (m, 4H); LCMS: 434 [M+H].

E22.35. Synthesis of1′-[3-(4-chlorophenoxy)propyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 150)

Compound 150 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione and1-chloro-4-(3-iodopropoxy)benzene and conditions outlined in procedureV. M.p.=130-132° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 7.92-7.87 (m, 1H),7.82-7.74 (m, 2H), 7.6-7.52 (m, 1H), 7.36-7.18 (m, 2H), 7.0-6.92 (m,2H), 4.1-3.95 (m, 2H), 3.07 (s, 2H), 2.83-2.72 (m, 2H), 2.55-2.48 (m,2H), 2.4-2.25 (m, 2H), 2.05-1.75 (m, 6H); LCMS: 470 [M+H].

E22.36. Synthesis of1′-[3-(4-fluorophenoxy)propyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 151)

Compound 151 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione and1-fluoro-4-(3-iodopropoxy)benzene and conditions outlined in procedureV. M.p.=164-165° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 7.92-7.87 (m, 1H),7.82-7.76 (m, 2H), 7.6-7.52 (m, 1H), 7.18-7.06 (m, 2H), 6.97-6.9 (m,2H), 4.03-3.95 (m, 2H), 3.07 (s, 2H), 2.82-2.72 (m, 2H), 2.55-2.48 (m,2H), 2.4-2.25 (m, 2H), 2.05-1.75 (m, 6H); LCMS: 454 [M+H].

E22.37. Synthesis of1′-isopropylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 152)

Compound 152 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,2-bromopropane and conditions outlined in procedure V. M.p.=197-198° C.;400 MHz ¹H NMR (DMSO-d) δ: 7.92-7.88 (m, 1H), 7.82-7.74 (m, 2H),7.6-7.52 (m, 1H), 3.06 (s, 2H), 2.8-2.63 (m, 3H), 2.6-2.48 (m, 2H),2.1-1.94 (m, 2H), 1.85-1.7 (m, 2H), 1.01 (d, J=3.1 Hz, 6H); LCMS: 344[M+H].

Example 23 Procedure W

E23.1. Synthesis of1′-(3-phenylpropyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 153)

To a solution ofspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (0.566 g,1.88 mmol) in acetonitrile (30 mL) was added triethylamine (0.80 mL,5.64 mmol) followed by (3-bromopropyl)benzene (0.747 g, 3.76 mmol). Thereaction was stirred at 70° C. for 3 hours. The solvent was thenevaporated under reduced pressure. The residue was dissolved indichloromethane (30 mL) and the organic layer was washed with water (30mL). The organic extract was dried with Na₂SO₄ and concentrated underreduced pressure. The crude product was purified by flash columnchromatography (SiO₂, 8% CH₃OH in dichloromethane). The product obtainedafter the chromatography was further purified by crystallization fromhexanes and dichloromethane to give the desired product as a purplesolid (0.405 g, 51%). M.p.=112-114° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 7.90(d, J=7.6 Hz, 1H), 7.78 (d, J=3.2 Hz, 2H), 7.58-7.54 (m, 1H), 7.29-7.22(m, 2H), 7.21-7.14 (m, 3H), 3.07 (s, 2H), 2.74 (m, 2H), 2.60 (t, J=7.6Hz 2H), 2.37-2.27 (m, 4H), 2.05-1-97 (m, 2H), 1.85-1.71 (m, 4H); LCMS:420 [M+H]; Calc. for C₂₅H₂₅NO₃S: C, 71.51, H, 6.005, N, 3.338; Found C,72.08, H, 5.35, N, 3.43.

E23.2. Synthesis of1′-(3-phenoxypropyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 144)

Compound 144 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,bromo-3-phenoxypropane and conditions outlined in procedure W.M.p.=127-129° C.:; 400 MHz ¹H NMR (DMSO-d₆): 7.89 (d, J=7.6 Hz, 1H),7.81-7.78 (m, 2H), 7.57 (dddd, J=2.4, 2.6, 5.2, 5.6 Hz, 2H), 7.28 (dd,J=6.8, 7.6 Hz, 2H), 6.94-6.86 (m, 4H), 4.01 (t, J=6.4 Hz, 2H), 3.08 (s,2H), 2.77 (d, J=12.0 Hz, 2H), 2.55-2.47 (m, 2H), 2.34 (t, J=10.4 Hz,2H), 2.00 (d, J=12.6 Hz, 2H), 1.903 (d, J=6.8 Hz, 2H), 1.81 (dt, J=4.0,12.2 Hz, 2H); LCMS: 436 [M+H].

E23.3. Synthesis of1′-(4-fluorobenzyl)-8-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 154)

Compound 154 was synthesized using8-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,1-(bromomethyl)-4-fluorobenzene ad conditions outlined in procedure W.Mp.=219-221° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 7.64 (d, J=8.4 Hz, 1H),7.37-7.27 (m, 4H), 7.15 (dd, J=8.8, 8.8 Hz, 2H), 3.88 (s, 3H), 3.54 (s,2H), 3.05 (s, 2H), 2.69 (d, J=11.6 Hz, 2H), 2.36 (dd, J=10.4 Hz, 2H),1.98 (d, J=13.2 Hz, 2H), 1.81 (dd, J=10.4, 10.4 Hz, 2H); LCMS: 440[M+H].

E23.4. Synthesis of1′-(2-phenylethyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 155)

Compound 155 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione.(2-bromoethyl)-benzene and conditions outlined in procedure W.M.p.=117-118° C.; 300 MHz ¹H NMR (CDCl₃) δ: 8.06-8.03 (m, 1H), 7.78-7.75(m, 1H), 7.68-7.63 (m, 1H), 7.51-7.45 (m, 1H), 7.32-7.26 (m, 2H),7.23-7.20 (m, 3H), 2.94-2.82 (m, 6H), 2.73-2.67 (m, 2H), 2.18-2.14 (m,2H), 2.83-2.64 (m, 2H), 1.96-1.86 (m, 2H); LCMS: 406 [M+H].

E23.5. Synthesis of9-bromo-1′-(4-fluorobenzyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 156)

Compound 156 was synthesized using9-bromospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,1-(bromomethyl)-4-fluorobenzene and conditions outlined in generalprocedure W. M.p.=210-211° C.; 400 MHz ¹H NMR (CDCl₃) δ: 7.91-7.88 (m,1H), 7.84-7.83 (m, 1H), 7.65-7.62 (m, 1H), 7.30-7.26 (m, 3H), 7.05-7.00(m, 2H), 3.58 (s, 2H), 2.93 (s, 2H), 2.76-2.72 (m, 2H), 2.50-2.46 (m,2H), 2.13-2.05 (m, 2H), 1.94-1.83 (m, 2H); LCMS: 488 [M+H].

E23.6. Synthesis of1′-[2-(4-chlorophenoxy)ethyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 145)

Compound 145 was synthesized Usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4-piperidine]-5,6-dione,1-(2-bromoethoxy)-4-chlorobenzene and conditions outlined in generalprocedure W. M.p.=131-133° C.; 400 MHz ¹H NMR (CDCl₃) δ: 7.95-7.87 (m,1H), 7.83-7.67 (iii, 2H), 7.62-7.52 (m, 1H), 7.31 (d, J=6 Hz, 2H), 6.97(d, J=6 Hz, 2H), 4.18-4.05 (m, 2H), 3.08 (s, 2H), 2.90-2.75 (m, 4H),2.57-2.48 (m, 2H), 2.08-1.92 (m, 2H), 1.88-1.76 (m, 2H); LCMS: 456[M+H].

Example 24 Procedure X

E24.1. Synthesis of1′-[3-(4-tert-butylphenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 157)

To a mixture ofspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (0.15 g,0.5 mmol) in acetonitrile (3.0 mL) was added2-[(4-tert-butylphenoxy)methyl]oxathiine (0.11 g, 0.55 mmol) followed bylithium perchlorate (0.058 g, 0.55 mmol). The reaction mixture wasstirred at 80° C. for 16 hours. The solvent was removed under vacuum.The crude product was purified by flash column chromatography (SiO₂,100% EtOAc to 2% methanol in EtOAc) to give the desired product as apurple solid (0.072 g, 29%). M.p.=137-140° C.; 400 MHz ¹H NMR (CDCl₃) δ:8.05 (d, 1H), 7.75 (d, 1H), 7.65 (t, 1H), 7.5 (t, 1H), 7.35 (d, 2H), 6.9(d, 2H), 4.15 (m, 1H), 4.0 (d, 2H), 2.95 (m, 3H), 2.8 (m, 2H), 2.65 (m,2H), 2.55 (t, 2H), 2.15 (d, 2H), 1.9 (m, 2H), 1.3 (s, 9H); LCMS: 508[M+H].

E24.2. Synthesis of1′-(2-hydroxy-3-phenoxypropyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 158)

Compound 158 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,2-(phenoxyethyl)oxirane and conditions outlined in procedure X.M.p.=174-176° C.; 400 MHz ¹H NMR (CDCl₃): 8.05 (d, 1H), 7.75 (d, 1H),7.65 (t, 1H), 7.5 (t, 1H), 7.15 (m, 2H), 6.95 (t, 1H), 6.9 (d, 2H), 4.15(m, 1H), 4.0 (d, 2H), 2.95 (m, 3H), 2.8 (m, 2H), 2.65 (m, 2H), 2.55 (t,2H), 2.15 (d, 2H), 1.9 (m, 2H); LCMS: 452 [M+H].

E24.3. Synthesis of1′-(2-hydroxy-2-methylbut-3-en-1-yl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 159)

Compound 159 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,2-methyl-2-vinyloxirane and conditions outlined in procedure X.M.p.=74-77° C.; 400 MHz ¹H NMR (CDCl₃) δ: 8.05 (d, 1H), 7.75 (d, 1H),7.65 (t, 1H), 7.5 (t, 1H), 5.9 (dd, 1H), 5.35 (d, 1H), 5.05 (d, 1H),3.0-2.7 (m, 4H), 2.6 (m, 4H), 2.45 (d, 1H), 2.1 (t, 2H), 1.9-1.75 (m,2H), 1.2 (s, 3H); LCMS: 386 [M+H].

E24.4. Synthesis of1′-(4,4,4-trifluoro-2-hydroxybutyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 160)

Compound 160 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,2-(2,2,2-trifluoroethyl)oxirane and conditions outlined in procedure X.M.p.=145-148° C. 400 MHz ¹H NMR (CDCl₃) δ: 8.05 (d, 1H), 7.75 (d, 1H),7.65 (t, 1H), 7.5 (t, 1H), 4.05 (m, 1H), 3.5 (s, 1H), 2.95 (m, 3H),2.85-2.7 (m, 2H), 2.6-2.3 (m, 4H), 2.2-2.1 (m, 3H), 2.0-1.9 (m, 2H);LCMS: 428 [M+H].

E24.5. Synthesis of1′-(2-hydroxycyclopentyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 161)

Compound 161 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,6-oxabicyclo[3.1.0]hexane and conditions outlined in procedure X.M.p.=110-113° C.; 400 MHz ¹H NMR (CDCl₃) δ: 8.05 (d, 1H), 7.75 (d, 1H),7.65 (t, 1H), 7.5 (t, 1H), 4.1 (m, 1H), 3.1 (d, 1H), 2.95 (s, 1H), 2.9(d, 1H), 2.7-2.5 (m, 3H), 2.2-1.85 (m, 8H), 1.8-1.5 (m, 4H); LCMS: 386[M+H].

E24.6. Synthesis of1′-(2-hydroxyhexyl)spiro[naphtho[2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 162)

Compound 162 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,2-butyloxirane and conditions outlined in procedure X. M.p.=160-163° C.;400 MHz ¹H NMR (CDCl₃) δ: 8.05 (d, 1H), 7.75 (d, 1H), 7.65 (t, 1H), 7.5(t, 1H), 3.7 (m, 1H), 2.95 (m, 3H), 2.8-2.7 (m, 2H), 2.5-2.35 (m, 3H),2.15 (d, 2H), 1.95-1.8 (m, 2H), 1.5-1.3 (m, 6H), 0.9 (t, 3H); LCMS: 402[M+H].

E24.7. Synthesis of1′-(2-hydroxy-3-phenylpropyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 163)

Compound 163 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,2-benzyloxirane and conditions outlined in procedure X. M.p.=70-73° C.;400 MHz ¹H NMR (CDCl₃) δ: 8.05 (d, 1H), 7.75 (d, 1H), 7.65 (t, 1H), 7.5(t, 1H), 7.35-7.2 (m, 5H), 3.95 (m, 1H), 2.95-2.8 (m, 5H), 2.75-2.65 (m,3H), 2.5-2.35 (m, 3H), 2.1 (d, 2H), 1.95-1.75 (m, 2H); LCMS: 436 [M+H].

E24.8. Synthesis of1′-[3-(4-fluorophenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 164)

Compound 164 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,2-[(4-fluorophenoxy)methyl]oxathiine and conditions outlined inprocedure X. M.p.=163-167° C.; 400 MHz ¹H NMR (CDCl₃) δ: 8.05 (d, 1H),7.75 (d, 1H), 7.65 (t, 1H), 7.5 (t, 1H), 6.95 (t, 2H), 6.85 (m, 2H),4.15 (m, 1H), 3.95 (d, 2H), 3.0-2.9 (m, 3H), 2.8 (d, 2H), 2.7-2.6 (m,2H), 2.55 (t, 2H), 2.15 (d, 2H), 1.95-1.85 (m, 2H); LCMS: 470 [M+H].

E24.9. Synthesis of1′-[3-(2-furylmethoxy)-2-hydroxypropyl]spiro[naphtho[2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 165)

Compound 165 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,2-[(oxiran-2-ylmethoxy)methyl]furan and conditions outlined in procedureX. M.p.=143-145° C.; LCMS: 456 [M+H].

E24.10. Synthesis of1′-(2-hydroxy-3-morpholin-4-ylpropyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 166)

Compound 166 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,4-(oxiran-2-ylmethyl)morpholine and conditions outlined in procedure X.M.p.=75-78° C.; 400 MHz ¹H NMR (CDCl₃) δ: 8.05 (d, 1H), 7.75 (d, 1H),7.65 (t, 1H), 7.5 (t, 1H), 3.9 (m, 1H), 3.7 (m, 5H), 2.95 (s, 1H), 2.9(t, 2H), 2.7-2.3 (m, 1H), 2.15 (d, 2H), 1.9 (q, 2H); LCMS: 445 [M+H].

E24.11. Synthesis of1′-(2-hydroxy-2-phenylethyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 167)

Compound 167 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4-piperidine]-5,6-dione,2-phenyloxirane and conditions outlined in procedure X. M.p.=193-195°C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 8.09-7.75 (m, 3H), 7.6-7.5 (m, 1H),7.4-7.2 (m, 5H), 5.03 (br. s, 1H), 4.93 (br. s, 1H), 3.07 (s, 2H),2.9-2.78 (m, 2H), 2.65-2.45 (m, 4H), 2.05-1.7 (m, 4H); LCMS: 422 [M+H].

E24.12. Synthesis of1′-(2-hydroxybutyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 168)

Compound 168 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,44′-piperidine]-5,6-dione,2-ethyloxirane and conditions outlined in procedure X. M.p.=180-182° C.;400 MHz ¹H NMR (DMSO-d₆) δ: 7.9 (m, 1H), 7.75 (m, 2H), 7.55 (m, 1H), 4.2(s, 1H), 3.5 (br s, 1H), 3.05 (s, 2H), 2.7 (br s, 2H), 2.45-2.25 (m,4H), 1.9 (m, 2H), 1.8 (m, 2H), 1.5-1.4 (m, 1H), 1.3-1.2 (m, 1H), 0.85(m, 3H); LCMS: 374 [M+H].

E24.13. Synthesis of1′-(2-hydroxy-3-isopropoxypropyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 169)

Compound 169 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,2-(isopropoxymethyl)oxathiine and conditions outlined in procedure X.M.p.=97-99° C. 400 MHz ¹H NMR (DMSO-d₆) δ: 7.95-7.9 (m, 1H), 7.94-7.7(m, 2H), 7.65-7.5 (m, 1H), 4.42 (br. s, 1H), 3.72 (br. s, 1H), 3.6-3.45(m, 1H), 3.35-3.2 (m, 2H), 3.07 (s, 2H), 2.8 (m, 2H), 2.5-2.2 (m, 4H),2.05-1.7 (m, 4H), 1.07 (d, J=5.2 Hz, 6H); LCMS: 418 [M+H].

E24.14. Synthesis of1′-[3-(4-ethylphenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 170)

Compound 170 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,2-[(4-ethylphenoxy)methyl]oxirane and conditions outlined in procedureX. LCMS: 480 [M+H]; R_(t)=1.09 min.

E24.15. Synthesis of1′-[3-(benzyloxy)-2-hydroxypropyl]spiro[naphtho[12-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 171)

Compound 171 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,2-[(benzyloxy)methyl]oxirane and conditions outlined in procedure X.LCMS: 466 [M+H]; R_(t)=1.01 min.

E24.16. Synthesis of1′-[3-(2-chlorophenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 172)

Compound 172 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,2-[(2-chlorophenoxy)methyl]oxirane and conditions outlined in procedureX. LCMS: 486 [M+H]; R_(t)=1.04 min.

E24.17. Synthesis of1′-[2-hydroxy-3-(2-methylphenoxy)propyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 173)

Compound 173 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,2-[(2-methylphenoxy)methyl]oxirane and conditions outlined in procedureX. LCMS: 466 [M+H]; R_(t)=1.05 min.

E24.18. Synthesis of1′-(2-hydroxy-3-isobutoxypropyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 174)

Compound 174 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,2-(isobutoxymethyl)oxirane and conditions outlined in procedure X. LCMS:432 [M+H]; R_(t)=0.97 min.

E24.19. Synthesis of1′-[2-hydroxy-3-(4-methoxyphenoxy)propyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 175)

Compound 175 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,2-[(4-methoxyphenoxy)methyl]oxirane and conditions outlined in procedureX. LCMS: 482 [M+H]; R_(t)=0.99 min.

E24.20. Synthesis of1′-[3-(4-chlorophenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 176)

Compound 176 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,2-[(4-chlorophenoxy)methyl]oxathiine and conditions outlined inprocedure X. LCMS: 486 [M+H]; R_(t)=1.06 min.

E24.21. Synthesis of1′-(2-hydroxy-2-phenylpropyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 177)

Compound 177 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,2-methyl-2-phenyloxirane and conditions outlined in general procedure X.M.p.=117° C. (dec); 400 MHz ¹H NMR (DMSO-d₆) δ: 7.88 (d, J=8 Hz, 1H),7.77 (d, J=4 Hz, 2H), 7.56 (d, J=4 Hz, 1H), 7.49 (d, J=7.2 Hz, 2H), 7.30(t, J=7.2 Hz, 2H), 7.19 (t, J=7.2 Hz, 1H), 4.84 (bs, 1H), 3.05 (s, 2H),2.72-2.34 (m, 2H), 1.96-1.83 (m, 4H), 1.80-1.57 (m, 4H), 1.47 (s, 3H).LCMS: 436 [M+H].

E24.22. Synthesis of1′-[3-(4-chlorophenyl)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 178)

Compound 178 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,2-(4-chlorobenzyl)oxirane and conditions outlined in procedure X.M.p.=195-196° C.; 300 MHz ¹H NMR (CDCl₃) δ: 8.05-8.02 (m, 1H), 7.75-7.72(m, 1H), 7.67-7.62 (m, 1H), 7.50-7.45 (m, 1H), 7.28-7.26 (m, 2H),7.18-7.16 (m, 2H), 3.95-3.90 (m, 1H), 2.93 (s, 1H), 2.89-2.82 (m, 2H),2.83-2.64 (m, 4H), 2.47-2.39 (m, 4H), 2.13 (d, J=13.8 Hz, 2H), 1.90-1.82(m, 2H); LCMS: 470 [M+H].

E24.23. Synthesis of1′-(2-hydroxy-2-methyl-3-phenylpropyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 179)

Compound 179 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,2-benzyl-2-methyloxirane and conditions outlined in procedure X.M.p.=186-187° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 7.89 (d, J=7.8 Hz, 1H),7.82-7.76 (m, 2H), 7.64-7.54 (m, 1H), 7.28-7.16 (m, 5H), 4.22 (s, 1H),4.11 (q, J=5.1 Hz, 1H), 3.38 (d, J=1.1 Hz, 1H), 3.17 (d, J=5.5 Hz, 3H),3.08 (s, 2H), 2.94-2.76 (m, 2H), 2.63-2.72 (m, 2H), 2.41-2.20 (m, 2H),2.02-1.94 (m, 2H), 1.92-1.80 (m, 2H). LCMS: 450 [M+H].

Example 25 Procedure Y

The chiral benzyloxiranes were synthesized using the procedure outlinedin Schaus et. al J. Am. Chem. Soc. 124 (7) 2002, 1307-1315. The chiralphenoxymethyloxiranes were synthesized using chiral glycidol (SigmaAldrich), DIAD, triphenylphosphine and the corresponding phenols andprocedure outline in Steffan et. al. Bioorg. Med. Chem. Lett. 2002, 12,2957-2961.

E25.1. Synthesis of1′-[(2S)-3-(4-fluorophenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 180)

To a mixture ofspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (1.0 g3.32 mmol) in acetonitrile (12.0 mL) was added(2S)-2-[(4-fluorophenoxy)methyl]oxirane (0.614 g, 3.65 mmol) followed bylithium perchlorate (0.388 g, 3.65 mmol). The reaction mixture wasstirred at 80° C. for 2 hours. The reaction was cooled to roomtemperature and dichloromethane (100 mL) added to it. The reaction wasthen washed with water (100 mL). The organic layer was separated, washedwith water, dried with sodium sulfate and concentrated under vacuum. Thecrude product vas purified by flash column chromatography (SiO₂, 80%EtOAc in dichloromethane to 100% EtOAc) to give the desired product as apurple solid (0.73 g, 45%). M.p.=174-175° C.; 400 MHz ¹H NMR (CDCl₃) δ:8.06 (dd, J=1.6, 7.6 Hz, 1H), 7.79-7.75 (m, 1H), 7.66 (dt, J=1.6, 7.6Hz, 1H), 7.5 (dt, J=1.6, 7.6 Hz, 1H), 7.05-6.94 (m, 2H), 6.9-6.84 (m,2H), 4.18-4.1 (m, 1H), 4.0-3.94 (m, 2H), 3.02-2.92 (m, 1H), 2.96 (s,2H), 2.86-2.76 (m, 2H), 2.72-2.62 (m, 2H), 2.6-2.5 (m, 2H), 2.2-2.12 (m,2H), 1.98-1.82 (m, 2H); LCMS: 470 [M+H]; enantiomeric excess determinedfrom chiral HPLC: 98%; Chiral HPLC R_(t)=30.54

E25.2. Synthesis of1′-[(2R)-3-(4-fluorophenoxy)-2-hydroxypropyl]spiro[naphtho[1.2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 181)

Compound 181 was synthesized usingspiro[naphtho[2,1-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,(2R)-2-[(4-fluorophenoxy)methyl]oxirane and conditions outlined inprocedure Y. M.p.=176-177° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 7.90 (d,J=7.6 Hz, 1H), 7.82-7.76 (m, 2H), 7.60-7.50 (m, 1H), 7.14-7.08 (m, 2H),6.98-6.93 (m, 2H), 4.88 (d, J=4.8 Hz, 1H), 4.00-3.94 (m, 2H), 3.88-3.82(m, 1H), 3.07 (s, 2H), 2.87-2.74 (m, 2H), 2.55-2.40 (m, 4H), 2.03-1.95(m, 2H), 1.86-1.76 (m, 2H); LCMS: 470 [M+H]; enantiomeric excessdetermined from chiral HPLC: 98%; Chiral HPLC R_(t)=62.58 min.

E25.3. Synthesis of1′-[(2S)-3-(4-chlorophenoxy)-2-hydroxypropyl]spiro[naphtho[2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 182)

Compound 182 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,(2S)-2-[(4-chlorophenoxy)methyl]oxathiine and conditions outlined inprocedure Y. M.p.=138-140° C.; 400 MHz ¹H NMR (CDCl₃) δ: 8.06 (dd,J=7.7, 1.5 Hz, 1H), 7.77 (d, J=7.7 Hz, 1H), 7.67 (td, J=7.7, 1.1 Hz,1H), 7.49 (td, J=7.5, 1.1 Hz, 1H), 7.28-7.21 (m, 2H), 6.88-6.82 (m, 2H),4.17-4.08 (m, 1H), 4.02-3.94 (m, 2H), 3.02-2.92 (m, 1H), 2.95 (s, 2H),2.84-2.76 (m, 2H), 2.71-2.61 (m, 2H), 2.54 (td, J=11.5, 2.4 Hz, 1H),2.17 (br. d, J=13.9 Hz, 2H), 1.98-1.82 (m, 2H); LCMS: 486 [M+H];enantiomeric excess determined from chiral HPLC: 98%; Chiral HPLCR_(t)=62.95 min.

E25.4. Synthesis of1′-[(2R)-3-(4-chlorophenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 183)

Compound 183 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,(2R)-2-[(4-chlorophenoxy)methyl]oxirane and conditions outlined inprocedure Y. M.p.=155-157° C.; 400 MHz ¹H NMR (CDCl₃) δ: 8.05 (dd,J=6.4, 7.6 Hz, 1H), 7.76 (d, J=7.7 Hz, 1H), 7.68-7.64 (m, 1H), 7.51-7.47(m, 1H), 7.25-7.22 (m, 2H), 6.86-6.84 (m, 2H), 4.14-4.11 (m, 1H),3.98-3.96 (m, 2H), 2.94 (brs, 3H), 2.80-2.77 (m, 2H), 2.70-2.62 (m, 2H),2.56-2.50 (m, 1H), 2.17 (d, J=13.6 Hz, 2H), 1.96-1.84 (m, 2H); LCMS: 486[M+H]; enantiomeric excess determined from chiral HPLC: 98%; Chiral HPLCR_(t)=33.67 min.

E25.5. Synthesis of1′-[(2S)-3-(4-tert-butylphenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 184)

Compound 184 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4-piperidine]-5,6-dione,(2S)-2-[(4-tert-butylphenoxy)methyl]oxirane and conditions outlined inprocedure Y. M.p.=155-157° C.; 400 MHz ¹H NMR (CDCl₃) δ: 8.06 (dd, J=1.2and 8 Hz, 1H), 7.77 (dd, J=1.2 and 8 Hz, 1H), 7.67 (dt, J=1.2 and 8 Hz,1H), 7.49 (dt, J=1.2 and 8 Hz, 1H), 7.31 (d, J=9.2 Hz, 2H), 6.86 (d,J=8.8 Hz, 2H), 4.10-4.17 (m, 1H), 4.00 (dd, J=1.2 and 4.8 Hz, 2H),2.99-2.95 (s, 3H), 2.74-2.86 (m, 2H), 2.64-2.7 (m, 2H), 2.51-2.6 (m,1H), 2.13-2.2 (m, 2H), 1.84-1.98 (m, 2H), 1.3 (s, 9H); LCMS: 508 [M+H];enantiomeric excess determined from chiral HPLC: 98%; Chiral HPLCR_(t)=50.98 min.

E25.6. Synthesis of1′-[(2R)-3-(4-tert-butylphenoxy)-2-hydroxypropyl]spiro[naphtho[2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 185)

Compound 185 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,(2R)-2-[(4-tert-butylphenoxy)methyl]oxirane and conditions outlined inprocedure Y. M.p.=150-152° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 7.89 (d,J=7.2 Hz, 1H), 7.79 (m, 2H), 7.56 (m, 1H), 7.28 (d, J=8 Hz, 2H), 6.85(d, J=8 Hz, 2H), 4.84 (s, 1H), 3.94 (m, 2H), 3.85 (m, 1H), 3.07 (s, 2H),2.80 (m, 2H), 2.45 (m, 4H), 1.99 (m, 2H), 1.82 (m, 2H); LCMS: 508 [M+H];enantiomeric excess determined from chiral HPLC: 98%; Chiral HPLCR_(t)=35.55 min.

E25.7. Synthesis of1′-[(2R)-2-hydroxy-3-phenylpropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 186)

Compound 186 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,(2R)-2-benzyloxirane and conditions outlined in procedure Y. M.p.=82-84°C.; 400 MHz ¹H NMR (DMSO) δ: 7.92-7.88 (m, 1H), 7.8-7.74 (m, 2H),7.6-7.52 (m, 1H), 7.3-7.14 (m, 5H), 4.44 (brd, J=4.4 Hz, 1H), 3.9-3.8(m, 1H), 3.07 (s, 2H), 2.82-2.7 (m, 3H), 2.64-2.56 (m, 1H), 2.46-2.28(m, 4H), 2.04-1.94 (m, 2H), 1.88-1.76 (m, 2H); LCMS: 436 [M+H];enantiomeric excess determined from chiral HPLC: >99%; Chiral HPLCR_(t)=50.74 min.

E25.8. Synthesis of1′-[(2S)-2-hydroxy-3-phenylpropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 187)

Compound 187 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,(2S)-2-benzyloxirane and conditions outlined in procedure Y.M.p.=149-150° C.; 400 MHz ¹H NMR (CDCl₃) δ: 8.04 (dd, J=7.8, 1.2 Hz,1H), 7.73 (dd, J=7.8, 0.8 Hz, 1H), 7.64 (td, J=7.6, 1.2 Hz, 1H), 7.48(td, J=7.4, 1.2 Hz, 1H), 7.34-7.20 (m, 5H), 4.02-3.94 (m, 1H), 2.93 (s,2H), 2.87 (dd, J=13.3, 6.8 Hz, 2H), 2.78-2.66 (m, 3H), 2.50-2.38 (m,3H), 2.18-2.08 (m, 2H), 1.94-1.78 (m, 2H); LCMS: 436 [M+H]; enantiomericexcess determined by chiral HPLC: >99%; Chiral HPLC R_(t)=63.08 min.

E25.9. Synthesis of9-bromo-1′-[(2S)-2-hydroxy-3-phenylpropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 188)

Compound 188 was synthesized using9-bromospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,(2S)-2-benzyloxirane and conditions outlined in procedure Y. M.p.=82-83°C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 7.82-7.76 (m, 3H), 7.29-7.21 (m, 4H),7.19-7.14 (m, 1H), 4.47-4.44 (m, 1H), 3.89-3.82 (m, 1H), 3.08 (s, 2H),2.82-2.69 (m, 3H), 2.63-2.54 (m, 1H), 2.42-2.27 (m, 4H), 2.20-1.94 (m,2H), 1.86-1.77 (m, 2H); LCMS: 514 [M+H].

E25.10. Synthesis of9-bromo-1′-[(2S)-3-(4-tert-butylphenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 189)

Compound 189 was synthesized using9-bromospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,(2S)-2-[(4-tert-butylphenoxy)methyl]oxathiine and conditions outlined inprocedure Y. M.p.=150-152° C.; 400 MHz ¹H NMR (CDCl₃) δ: 7.92-7.89 (m,1H), 7.87-7.85 (m, 1H), 7.65-7.62 (m, 1H), 7.33-7.29 (m, 2H), 6.89-6.85(m, 2H), 4.20-4.10 (m, 1H), 4.03-3.98 (m, 2H), 2.96 (s, 2H), 2.83-2.73(m, 2H), 2.73-2.62 (m, 2H), 2.62-2.50 (m, 1H), 2.20-2.12 (m, 2H),2.00-1.85 (m, 2H), 1.29 (s, 9H); LCMS: 586 [M+H].

E25.11. Synthesis of9-bromo-1′-[(2S)-3-(4-chlorophenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 190)

Compound 190 vas synthesized using9-bromospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,(2S)-2-[(4-chlorophenoxy)methyl]oxathiine and conditions outlined inprocedure Y. M.p.=150-152° C.; 400 MHz ¹H NMR (CDCl₃) δ: 7.92-7.89 (m,1H), 7.87-7.85 (m, 1H), 7.65-7.62 (m, 1H), 7.27-7.22 (m, 2H), 6.88-6.84(m, 2H), 4.20-4.08 (m, 1H), 4.03-3.95 (m, 2H), 2.96 (s, 3H), 2.85-2.74(m, 2H), 2.74-2.60 (m, 2H), 2.60-2.50 (m, 1H), 2.21-2.12 (m, 2H),2.00-1.85 (m, 2H); LCMS: 564 [M+H].

E25.12. Synthesis of1′-[(2S)-3-(4-tert-butylphenoxy)-2-hydroxypropyl]-9-fluorospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 191)

Compound 191 was synthesized using9-fluorospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,(2S)-2-[(4-tert-butylphenoxy)methyl]oxathiine and conditions outlined inprocedure Y. M.p.=114-116° C., 400 MHz ¹H NMR (DMSO-d₆) δ: 7.99-7.95 (m,1H), 7.46-7.37 (m, 2H), 7.29-7.27 (d, J=8.60 Hz, 2H), 6.86-6.84 (d,J=8.99 Hz, 2H), 4.85 (br s, 1H), 3.96-3.4 (m, 2H), 3.86-3.84 (m, 1H),3.34 (s, 2H), 2.79-2.74 (m, 3H), 2.50-2.44 (m, 3H), 1.99-1.96 (m, 2H),1.83-1.81 (m, 2H), 1.24 (s, 9H); LCMS: 526 [M+H]

E25.13. Synthesis of1′-[(2S)-3-(4-tert-butylphenoxy)-2-hydroxypropyl]-9-chlorospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 192)

Compound 192 was synthesized using9-chlorospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,(2S)-2-[(4-tert-butylphenoxy)methyl]oxathiine and conditions outlined inprocedure Y. M.p.=94-97° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 7.89 (d, J=8.4Hz, 1H), 7.67-7.62 (m, 2H), 7.28 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz,2H), 4.86 (d, J=4.4 Hz, 1H), 4.0-3.92 (m, 2H), 3.87-3.83 (m, 1H), 3.08(s, 2H), 2.84-2.75 (m, 2H), 2.48-2.41 (m, 4H), 2.02-1.94 (m, 2H),1.86-1.76 (m, 2H), 1.25 (s, 9H); LCMS: 542 [M+H].

E25.14. Synthesis of9-chloro-1′-[(2S)-2-hydroxy-3-phenylpropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 193)

Compound 193 was synthesized using9-chlorospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,(2S)-2-benzyloxirane and conditions outlined in procedure Y. M.p.=92-96°C., 400 MHz ¹H NMR (CDCl₃) δ: 7.99-7.97 (d, J=8.21 Hz, 1H), 7.667-7.662(d, J=1.95 Hz, 1H), 7.46-7.43 (dd, J=1.56, 7.82 Hz, 1H), 7.33-7.23 (m,5H), 4.01-3.94 (m, 1H), 3.33 (br s, 1H), 2.93-2.82 (m, 4H), 2.74-2.70(m, 3H), 2.51-2.41 (m, 3H), 2.14-2.10 (d, J=13.7 Hz, 2H), 1.94-1.80 (m,2H); LCMS: 470 [M+H].

E25.15. Synthesis of9-chloro-1′-[(2R)-2-hydroxy-3-phenylpropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 194)

Compound 194 was synthesized using9-chlorospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,(2R)-2-benzyloxirane and conditions outlined in procedure Y. M.p.=92-93°C., 400 MHz ¹H NMR (CDCl₃) δ: 8.00-7.97 (d, J=8.21 Hz, 1H), 7.668-7.663(d, J=1.95 Hz, 1H), 7.46-7.43 (dd, J=1.95, 8.21 Hz, 1H), 7.33-7.23 (m,5H), 4.09-3.94 (m, 1H), 3.33 (br s, 1H), 2.88-2.82 (m, 4H), 2.75-2.70(m, 3H), 2.52-2.41 (m, 3H), 2.14-2.11 (d, J=12.9 Hz, 2H), 1.94-1.80 (m,2H); LCMS: 470 [M+H].

E25.16. Synthesis of1′-[(2R)-2-hydroxy-3-phenylpropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,3′-piperidine]-5,6-dione(Compound 195)

Compound 195 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,3′-piperidine]-5,6-dione,(2R)-2-benzyloxirane and conditions outlined in procedure Y. M.p.=65-67°C., 400 MHz ¹H NMR (CDCl₃) δ: 8.04-8.03 (br d, J=7.82 Hz, 1H), 7.73-7.60(m, 2H), 7.49-7.44 (m, 1H), 7.31-7.18 (m, 5H), 3.95-3.91 (m, 1H),3.18-2.91 (m, 3H), 2.78-2.53 (m, 5H), 2.45-2.33 (m, 2H), 2.03-1.70 (m,4H); LCMS: 436 [M+H].

E25.17. Synthesis of1′-[(2S)-2-hydroxy-3-phenylpropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,3′-piperidine]-5,6-dione(Compound 196)

Compound 196 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,3′-piperidine]-5,6-dione,(2S)-2-benzyloxirane and conditions outlined in procedure Y. M.p.=59-60°C., 400 MHz ¹H NMR (CDCl₃) δ: 8.05-8.03 (br d, J=7.43 Hz, 1H), 7.73-7.70(m, 1H), 7.65-7.60 (m, 1H), 7.52-7.44 (m, 1H), 7.31-7.18 (m, 5H),3.95-3.91 (m, 1H), 3.18-2.91 (m, 3H), 2.78-2.53 (m, 5H), 2.45-2.33 (m,2H), 2.03-1.71 (m, 4H); LCMS: 436 [M+H].

E25.18. Synthesis of1′-[(2S)-3-(4-tert-butylphenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,3′-piperidine]-5,6-dione(Compound 197)

Compound 197 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,3′-piperidine]-5,6-dione,(2S)-2-[(4-tert-butylphenoxy)methyl]oxathiine and conditions outlined inprocedure Y. M.p.=90-92° C., 400 MHz ¹H NMR (CDCl₃) δ: 8.04-8.02 (d,J=7.43 Hz, 1H), 7.75-7.73 (d, J=7.82 Hz, 1H), 7.63-7.58 (m, 1H),7.48-7.44 (m, 1H), 7.31-7.21 (m, 2H), 6.83-6.80 (m, 1H), 4.13-4.07 (m,1H), 3.15-2.96 (m, 3H), 2.82 (s, 1H), 2.65-2.50 (m, 5H), 2.04-1.73 (m,4H), 1.29 (s, 9H); LCMS: 508 [M+H].

E25.19. Synthesis of1′-{1-[(2S)-3-(4-tert-butylphenoxy)-2-hydroxypropyl]piperidine-4-yl}spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 198)

Compound 198 was synthesized using1′-piperidin-4-ylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dionebis-hydrochloride, (2S)-2-[(4-tert-butyl phenoxy)methyl]oxirane, hunig'sbase and conditions outlined in procedure Y. M.p.=190-193° C.; 400 MHz¹H NMR (CDCl₃) δ: 8.04-8.02 (m, 1H), 7.74-7.67 (m, 2H), 7.51-7.47 (m,1H), 7.30-7.28 (m, 2H), 6.85-6.83 (m, 2H), 4.30 (t, 1H), 4.02-3.94 (m,2H), 3.46-3.1 (m, 3H), 2.95-2.92 (m, 4H), 2.82 (d, 2H), 2.72 (t, 2H),2.65 (bs, 2H), 2.45 (t, 1H), 2.19 (d, 2H), 1.98-1.93 (m, 6H), 1.29 (s,9H); LCMS: 591 [M+H].

E25.20. Synthesis of1′-[(2R)-3-(4-tert-butylphenoxy)-2-hydroxypropyl]-9-phenylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 199)

Compound 199 was synthesized using9-phenyl-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,(2R)-2-[(4-tert-butylphenoxy)methyl]oxirane, hunig's base and conditionsoutlined in procedure Y. M.p.=94-97° C.; 400 MHz ¹H NMR (DMSO-d₆) δ:8.01 (d, J=1.6 Hz, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.88-7.85 (dd, 1H), 7.76(d, J=7.6 Hz, 2H), 7.58-7.49 (m, 3H), 7.28-7.26 (m, 2H), 6.84 (d, J=8.8Hz, 2H), 4.85 (s, 1H), 3.96-3.92 (m, 2H), 3.86-3.84 (m, 1H), 3.10 (s,2H), 2.82 (t, 2H), 2.46 (d, 4H), 2.04 (d, 2H), 1.84 (t, 2H), 1.20 (s,9H); LCMS: 584 [M+H].

E25.21. Synthesis of1′-[(2S)-2-hydroxy-3-(2-methylphenoxy)propyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 200)

Compound 200 was synthesized usingspiro[naphtha[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,(2S)-2-[(2-methylphenoxy)methyl]oxirane and conditions outlined inprocedure Y. M.p.=197-199° C.; 400 MHz ¹H NMR (CDCl₃) δ: 8.05 (dd, J=1.2and 7.6 Hz, 1H), 7.77 (dd, J=0.8 and 7.6 Hz, 1H), 7.67 (dt, J=1.6 and8.0 Hz, 1H), 7.48 (dt, J=1.2 and 7.6 Hz, 1H), 7.17-7.13 (m, 2H),6.90-6.82 (m, 2H), 4.20-4.14 (m, 1H), 4.06-3.98 (m, 2H), 3.00-2.95 (m,4H), 2.84-2.75 (m, 2H), 2.73-2.66 (m, 2H), 2.55 (dt, J=2.4 and 11.2 Hz,1H), 2.24 (s, 3H), 2.20-2.12 (m, 2H), 1.97-1.84 (m, 2H); LCMS: 466[M+H].

E25.22. Synthesis of1′-[(2R)-3-(4-tert-butylphenoxy)-2-hydroxypropyl]-8-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 201)

Compound 201 was synthesized using8-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,(2R)-2-[(4-tert-butylphenoxy)methyl]oxirane and conditions outlined inprocedure Y. M.p.=188-190° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 7.73 (d,J=8.6 Hz, 1H), 7.38 (d, J=7.6 Hz, 1H), 7.34 (d, J=2.8 Hz, 1H), 7.31 (d,J=3.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 2H), 6.85 (d, J=9.0 Hz, 1H), 4.86 (d,J=4.7 Hz, 1H), 4.00-3.81 (m, 1H), 3.87 (s, 3H), 3.05 (s, 2H), 2.86-2.73(m, 2H), 2.54-2.38 (m, 2H), 2.02-1.95 (m, 2H), 1.86-1.74 (m, 2H), 1.25(s, 9H). LCMS: 538 [M+H].

E25.23. Synthesis of1′-[(2S)-3-(4-tert-butylphenoxy)-2-hydroxypropyl]-8-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 202)

Compound 202 was synthesized using8-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,(2S)-2-[(4-tert-butylphenoxy)methyl]oxirane and conditions outlined inprocedure Y. M.p.=188-190° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 7.73 (d,J=8.6 Hz, 1H), 7.38 (d, J=7.6 Hz, 1H), 7.34 (d, J=2.8 Hz, 1H), 7.31 (d,J=3.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 2H), 6.85 (d, J=9.0 Hz, 1H), 4.86 (d,J=4.7 Hz, 1H), 4.00-3.81 (m, 1H), 3.87 (s, 3H), 3.05 (s, 2H), 2.86-2.73(m, 2H), 2.54-2.38 (m, 2H), 2.02-1.95 (m, 2H), 1.86-1.74 (m, 2H), 1.25(s, 9H). LCMS: 538 [M+H].

E25.24. Synthesis of1′-[(2S)-2-hydroxy-3-phenylpropyl]-8-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 203)

Compound 203 was synthesized using8-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,(2S)-2-benzyloxirane and conditions outlined in procedure Y.M.p.=146-147° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 7.73 (d, J=8.6 Hz, 1H),7.38 (d, J=7.6 Hz, 1H), 7.34 (d, J=2.8 Hz, 1H), 7.31 (d, J=3.0 Hz, 1H),7.28-7.12 (m, 4H), 4.43 (d, J=4.7 Hz, 1H), 3.84 (s, 3H), 3.03 (s, 2H),2.80-2.68 (m, 2H), 2.58 (dd, J=7.4, 14.0 Hz, 1H), 2.47-2.26 (m, 3H),1.99-1.90 (m, 2H), 1.87-1.72 (m, 2H). LCMS: 466 [M+H].

E25.25. Synthesis of1′-[(2R)-2-hydroxy-3-phenylpropyl]-8-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 204)

Compound 204 was synthesized using8-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,(2R)-2-benzyloxirane and conditions outlined in procedure Y.M.p.=145-147° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 7.73 (d, J=8.6 Hz, 1H),7.38 (d, J=7.6 Hz, 1H), 7.34 (d, J=2.8 Hz, 1H), 7.31 (d, J=3.0 Hz, 1H),7.28-7.12 (m, 4H), 4.43 (d, J=4.7 Hz, 1H), 3.84 (s, 3H), 3.03 (s, 2H),2.80-2.68 (m, 2H), 2.58 (dd, J=7.4, 14.0 Hz, 1H), 2.47-2.26 (m, 3H),1.99-1.90 (m, 2H), 1.87-1.72 (m, 2H). LCMS: 466 [M+H].

E25.26. Synthesis of1′-[(2S)-3-(4-chlorophenoxy)-2-hydroxypropyl]-8-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 205)

Compound 205 was synthesized using8-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,(2S)-2-[(4-chlorophenoxy)methyl]oxirane and conditions outlined inprocedure Y. M.p.=189-191° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 7.73 (d,J=8.6 Hz, 1H), 7.38 (d, J=7.6 Hz, 1H), 7.34 (d, J=2.8 Hz, 1H), 7.31 (dd,J=1.5, 6.8 Hz, 3H), 6.98 (d, J=3.5 Hz, 1H), 4.90 (d, J=4.7 Hz, 1H),4.05-3.92 (m, 2H), 3.87 (s, 3H), 3.05 (s, 2H), 2.86-2.74 (m, 2H),2.55-2.38 (m, 4H), 2.01-1.93 (m, 2H), 1.86-1.73 (m, 2H). LCMS: 516[M+H].

E25.27. Synthesis of1′-[(2S)-3-(4-fluorophenoxy)-2-hydroxypropyl]-8-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 206)

Compound 206 was synthesized using8-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,(2S)-2-[(4-fluorophenoxy)methyl]oxirane and conditions outlined inprocedure Y. M.p.=189-191° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 7.73 (d,J=8.6 Hz, 1H), 7.38 (d, J=7.6 Hz, 1H), 7.34 (d, J=2.8 Hz, 1H), 7.31 (dd,J=1.5, 6.8 Hz, 3H), 6.98 (d, J=3.5 Hz, 1H), 4.90 (d, J=4.7 Hz, 1H),4.05-3.92 (m, 2H), 3.87 (s, 3H), 3.06 (s, 2H), 2.87-2.72 (m, 2H),2.57-2.32 (m, 4H), 2.01-1.90 (m, 2H), 1.86-1.73 (m, 2H). LCMS: 500[M+H].

E25.28. Synthesis of1′-[(2S)-3-(4-ethylphenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 207)

Compound 207 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,(2S)-2-[(4-ethylphenoxy)methyl]oxirane and conditions outlined inprocedure Y. M.p.=137-138° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 7.90 (d, 1H,J=7.8 Hz), 7.82-7.78 (m, 2H), 7.57 (dt, 1H, J=2.0, 6.8 Hz), 7.10 (d, 2H,J=5.6 Hz), 6.85 (d, 2H, J=8.2 Hz), 4.86 (bs, 1H), 4.03-3.80 (m, 3H),3.07 (s, 2H), 2.88-2.74 (m, 2H), 2.58-2.41 (m, 2H), 2.02-1.94 (m, 2H),1.88-1.78 (m, 2H), 1.14 (t, J=7.9 Hz, 3H). LCMS: 480 [M+H].

E25.29. Synthesis of1′-[(2R)-2-hydroxy-3-phenylpropyl]-9-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 208)

Compound 208 was synthesized using9-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,(2R)-2-benzyloxirane using conditions outlined in procedure Y. M.p.=106°C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 7.88 (d, J=8.8 Hz, 1H), 7.08-7.28 (m,7H), 4.50 (brs, 1H), 3.93 (brs, 4H), 3.07 (s, 2H), 2.76 (M, 4H), 2.60(m, 2H), 2.33 (m, 2H), 1.95 (m, 2H), 1.83 (m, 2H); LCMS: 466 [M+H];

E25.30. Synthesis of1′-[(2S)-2-hydroxy-3-phenylpropyl]-9-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 209)

Compound 209 vas synthesized using9-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(2S)-2-benzyloxirane following conditions outlined in procedure Y.M.p.=110° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 7.92 (d, J=8.8 Hz, 1H),7.21-7.31 (m, 6H), 7.11 (m, 1H), 4.10 (m, 1H), 3.92 (s, 3H), 3.15 (s,2H), 3.10 (s, 2H), 2.76 (m, 4H), 2.60 (m, 2H), 2.22 (m, 2H), 1.95 (m,2H); LCMS: 466 [M+H].

E25.31. Synthesis of1′-[(2S)-3-(4-chlorophenoxy)-2-hydroxypropyl]-9-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 210)

Compound 210 was synthesized using9-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,(2S)-2-[(4-chlorophenoxy)methyl]oxirane and conditions outlined inprocedure Y. M.p.=109-110° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 7.88 (d,J=8.8 Hz, 1H), 7.32 (d, J=8.8 Hz, 2H), 7.21 (brs, 1H), 7.10 (dd, 1H),6.97 (d, J=9.2 Hz, 2H), 4.84 (s, 1H), 3.98 (brm, 6H), 3.07 (s, 2H), 2.80(m, 2H), 2.41 (m, 4H), 1.99 (m, 2H), 1.82 (m, 2H); LCMS: 516 [M+H].

E25.32. Synthesis of1′-[(2S)-3-(4-fluorophenoxy)-2-hydroxypropyl]-9-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 211)

Compound 211 vas synthesized using9-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,(2S)-2-[(4-fluorophenoxy)methyl]oxirane and conditions outlined inprocedure Y. M.p.=80-81° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 7.88 (d, J=8.8Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.09 (m, 3H), 6.95 (m, 2H), 4.85 (s,1H), 3.98 (brm, 6H), 3.07 (s, 2H), 2.80 (m, 2H), 2.41 (m, 4H), 1.99 (m,2H), 1.80 (m, 2H); LCMS: 500 [M+H].

E25.33. Synthesis of1′-[(2S)-3-(4-tert-butylphenoxy)-2-hydroxypropyl]-9-phenylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 212)

Compound 212 was synthesized using9-phenylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,(2S)-2-[(4-tert-butylphenoxy)methyl]oxirane and conditions outlined inprocedure Y. M.p.=151-152° C.; 400 MHz ¹H NMR (DMSO d₆) δ: 7.98 (m, 2H),7.86 (d, J=7.6 Hz, 1H), 7.76 (d, J=8.0 Hz, 2H), 7.53 (m, 3H), 7.28 (m,2H), 6.85 (m, 2H), 4.85 (brs, 1H), 3.98 (brm, 3H), 3.10 (s, 2H), 2.82(m, 2H), 2.44 (m, 4H), 2.0 (m, 2H), 1.80 (m, 2H), 1.20 (s, 9H); LCMS:584 [M+H].

E25.34. Synthesis of1′-[(2R)-3-(4-chlorophenoxy)-2-hydroxypropyl]-9-phenylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 213)

Compound 213 was synthesized using9-phenylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dioneand (2R)-2-[(4-chlorophenoxy)methyl]oxirane using conditions outlined inprocedure Y. M.p.=111-112° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 7.96 (brs,2H), 7.83 (d, J=8.0 Hz, 1H), 7.73 (d, J=8 Hz, 2H), 7.53 (t, J=7.2 Hz,2H), 7.47 (m 1H), 7.28 (m, 2H), 6.92 (m, 2H), 4.88 (brs, 1H), 3.95 (brm,2H), 3.84 (t, 8.8 Hz, 1H), 3.07 (s, 2H), 2.80 (m, 2H), 2.41 (m, 4H),1.98 (m, 2H), 1.80 (m, 2H); LCMS: 562 [M+H].

E25.35. Synthesis of1′-[(2S)-3-(4-tert-butylphenoxy)-2-hydroxypropyl]-9-morpholin-4-ylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 214)

Compound 214 was synthesized using9-morpholin-4-ylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,(2S)-2-[(4-tert-butylphenoxy)methyl]oxirane and conditions outlined inprocedure Y. M.p.=107-109° C.; 400 MHz ¹H NMR (DMSO d₆) δ: 7.74 (d,J=8.0 Hz, 1H), 7.25 (d, J=8.8 Hz, 2H), 7.18 (brs, 1H), 7.0 (d, J=8.8 Hz,1H), 6.83 (d, J=8.4 Hz, 2H), 4.85 (brs, 1H), 3.91 (m, 2H), 3.82 (m, 1H),3.74 (m, 4H), 3.43 (m, 4H), 3.05 (s, 2H), 2.76 (m, 2H), 2.43 (m, 4H),1.97 (m, 2H), 1.78 (m, 2H), 1.22 (s, 9H); LCMS: 593 [M+H].

E25.36. Synthesis of methyl(4-{[(2R)-3-(5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-yl)-2-hydroxypropyl]oxy}phenyl)acetate(Compound 215)

Compound 215 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, methyl{4-[(2R)-oxiran-2-ylmethoxy]phenyl}acetate and conditions outlined inprocedure Y. M.p.=122-124° C.; 400 MHz ¹H NMR (CDCl₃) δ: 8.06 (dd,J=8.1, 0.7 Hz, 1H), 7.70 (d, J=7.7 Hz, 1H), 7.67 (td, J=7.7, 0.7 Hz,1H), 7.50 (t, J=7.5 Hz, 1H), 7.20 (d, J=8.4 Hz, 2H), 6.89 (d, J=8.4 Hz,2H), 4.2-4.1 (m, 1H), 4.0 (d, J=4.8 Hz, 2H), 3.69 (s, 2H), 3.57 (s, 2H),3.0-2.9 (m, 1H), 2.95 (s, 3H), 2.84-2.74 (m, 2H), 2.69-2.62 (m, 2H),2.54 (td, J=10.4, 1.8 Hz, 1H), 2.2-2.12 (m, 2H), 1.98-1.84 (m, 2H);LCMS: 524 [M+H].

E25.37. Synthesis of1′-{(2S)-3-[(6-bromo-2-naphthyl)oxy]-2-hydroxypropyl}spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 216)

Compound 216 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,(2S)-2-{[(6-bromo-2-naphthyl)oxy]methyl}oxirane and conditions outlinedin procedure Y. M.p.=183-184° C.; 400 MHz ¹H NMR (CDCl₃) δ: 8.06 (dd,J=7.7, 0.7 Hz, 1H), 7.92 (d, J=1.2 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H),7.69-7.64 (m, 2H), 7.60 (d J=8.8 Hz, 1H), 7.52-7.47 (m, 2H), 7.20 (dd,J=9.2, 2.6 Hz, 1H), 7.12 (d, J=2.6 Hz, 1H), 4.25-4.18 (m, 1H), 4.12 (d,J=4.8 Hz, 2H), 3.04-2.92 (m, 1H), 2.96 (s, 2H), 2.90-2.80 (m, 2H),2.78-2.68 (m, 2H), 2.57 (t, J=10.4 Hz, 1H), 2.25-2.12 (m, 2H), 1.98-1.84(m, 2H); LCMS: 580 [M+H].

E25.38. Synthesis of9-bromo-1′-{(2S)-3-[(6-bromo-2-naphthyl)oxy]-2-hydroxypropyl}spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 217)

Compound 217 was synthesized using9-bromospiro[naphtho[1,2-b][1,4]oxathiine-2,4-piperidine]-5,6-dione,(2S)-2-{[(6-bromo-2-naphthyl)oxy]methyl}oxirane and conditions outlinedin procedure Y. M.p.=104-105° C.: 400 MHz ¹H NMR (CDCl₃) δ: 7.94-7.85(m, 3H), 7.70-7.56 (m, 3H), 7.54-7.47 (m, 1H), 7.23-7.17 (m, 1H), 7.12(d, J=2.6 Hz, 1H), 4.26-4.18 (m, 1H), 4.17-4.08 (m, 2H), 3.04-2.94 (m,1H), 2.96 (s, 2H), 2.90-2.78 (m, 2H), 2.76-2.66 (m, 2H), 2.56 (t, J=11.4Hz, 1H), 2.24-2.12 (m, 2H), 2.00-1.85 (m, 2H); LCMS: 660 [M+H].

E25.39. Synthesis of benzyl4-{[(2S)-3-(5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-yl)-2-hydroxypropyl]oxy}benzoate(Compound 218)

Compound 218 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, benzyl4-[(2S)-oxiran-2-ylmethoxy]benzoate and conditions outlined in procedureY. M.p.=83-84° C.; 400 MHz ¹H NMR (CDCl₃) δ: 8.08-8.00 (m, 3H), 7.76(dd, J=7.8, 0.8 Hz, 1H), 7.66 (td, J=7.6, 1.2 Hz, 1H), 7.49 (td, J=7.6,1.2 Hz, 1H), 7.46-7.32 (m, 5H), 6.97-6.92 (m, 2H), 5.34 (s, 2H),4.20-4.12 (m, 1H), 4.06 (d, J=5.6 Hz, 2H), 3.02-2.92 (m, 1H), 2.95 (s,2H), 2.84-2.76 (m, 2H), 2.72-2.62 (m, 2H), 2.55 (t, J=10.4 Hz, 1H),2.22-2.12 (m, 2H), 1.98-1.82, (m, 2H); LCMS: 586 [M+H].

E25.40. Synthesis of9-fluoro-1′-[(2R)-2-hydroxy-3-phenylpropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 219)

Compound 219 was synthesized using9-fluorospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidin]-5,6-dione,(2R)-2-benzyloxirane and conditions outlined in procedure Y. M.p.=76-77°C.; 400 MHz ¹H NMR (CDCl₃) δ: 8.08 (dd. J=8.6, 5.9 Hz, 1H), 7.37 (dd,J=9.4, 2.7 Hz, 1H), 7.34-7.28 (m, 2H), 7.27-7.21 (m, 3H), 7.14 (td,J=8.2, 2.7 Hz, 1H), 4.04-3.95 (m, 1H), 2.98-2.82 (m, 2H), 2.93 (s, 2H),2.79-2.66 (m, 3H), 2.54-2.37 (111, 3H), 2.16-2.08 (11, 2H), 1.97-1.80(m, 2H); LCMS: 454 [M+H].

E25.41. Synthesis of9-fluoro-1′-[(2S)-2-hydroxy-3-phenylpropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 220)

Compound 220 was synthesized using9-fluorospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,(25)-2-benzyloxirane and conditions outlined in procedure Y. M.p.=77-79°C.; 400 MHz ¹H NMR (CDCl₃) δ: 8.08 (dd, J=8.6, 5.9 Hz, 1H), 7.37 (dd,J=9.4, 2.7 Hz, 1H), 7.34-7.28 (m, 2H), 7.27-7.21 (m, 3H), 7.14 (td,J=8.2, 2.7 Hz, 1H), 4.04-3.95 (m, 1H), 2.98-2.82 (m, 2H), 2.93 (s, 2H),2.79-2.66 (m, 3H), 2.54-2.37 (m, 3H), 2.16-2.08 (m, 2H), 1.97-1.80 (m,2H); LCMS: 454 [M+H].

E25.42. Synthesis of1′-[(2S)-2-hydroxy-3-(2-naphthyloxy)propyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 221)

Compound 221 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,(2S)-2-[(2-naphthyloxy)methyl]oxathiine and conditions outlined inprocedure Y. M.p.=164-167° C., (DMSO-d₆) δ: 7.91-7.87 (m, 1H), 7.84-7.78(m, 5H), 7.6-7.52 (m, 1H), 7.48-7.4 (m, 1H), 7.38-7.3 (m, 2H), 7.2-7.14(m, 1H), 5.0-4.93 (m, 1H), 4.2-3.97 (m, 3H), 3.07 (s, 2H), 2.93-2.76 (m,2H), 2.63-2.4 (m, 4H), 2.06-1.93 (m, 2H), 1.9-1.78 (m, 2H); LCMS=502[M+H].

E25.43. Synthesis of9-bromo-1′-[(2R)-2-hydroxy-3-phenylpropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 222)

Compound 222 was synthesized using9-bromospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,(2R)-2-benzyloxirane and conditions outlined in procedure Y. M.p.=82-84°C., (DMSO-d₆) δ: 7.88-7.72 (m, 3H), 7.3-7.1 (m, 5H), 4.46-4.4 (m, 1H),3.9-3.8 (m, 1H), 3.08 (s, 2H), 2.82-2.67 (m, 3H), 2.63-2.55 (m, 1H),2.4-2.25 (m, 4H), 2.06-1.93 (m, 2H), 1.9-1.78 (m, 2H); LCMS=514 [M+H].

E25.44. Synthesis of9-bromo-1′-[(2R)-3-(4-tert-butylphenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 223)

Compound 223 was synthesized using9-bromospiro[naphtho[1,2-b][1,4]oxathiine-2,4-piperidine]-5,6-dione,(2R)-2-[(4-tert-butylphenoxy)methyl]oxathiine and conditions outlined inprocedure Y. 400 MHz ¹H NMR (DMSO) δ: 7.83 (s, 1H), 7.79 (m, 2H), 7.29(d, 2H), 6.86 (d, 2H), 4.86 (br s, 1H), 3.99-3.94 (m, 2H), 3.89-3.86 (m,1H), 3.19 (s, 2H), 2.87-2.72 (m, 2H), 2.56-2.50 (m, 2H), 2.47-2.35 (m,2H), 2.04-1.96 (m, 2H), 1.87-1.78 (m, 2H), 1.25 (s, 9H); LCMS: 587[M+H].

E25.45. Synthesis of1′-[(2R)-2-hydroxy-3-(2-methylphenoxy)propyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 224)

Compound 224 was synthesized usingspiro[naphtha[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,(2R)-2-[(2-methylphenoxy)methyl]oxirane and conditions outlined inprocedure Y. M.p.=191-193° C.; 400 MHz ¹H NMR (CDCl₃) δ: 8.06 (d, J=8.0Hz, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.67 (m, 1H), 7.49 (t, 1H), 7.17-7.13(m, 2H), 6.89-6.82 (m, 2H), 4.18-4.15 (m, 1H), 4.05-3.98 (m, 2H), 2.95(s, 3H), 2.80-2.75 (m, 2H), 2.70-2.66 (m, 2H), 2.57-2.51 (m, 1H), 2.24(s, 2H), 2.18-2.15 (m, 2H), 1.96-1.84 (m, 2H); LCMS: 466 [M+H].

Example 26 Procedure Z

E26.1. Synthesis of1′-[(2S)-3-(4-tert-butylphenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 184)

To a mixture ofspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (10.0 g,33.18 mmol) in absolute ethanol (100 mL) was added(2S)-2-[(4-tert-butylphenoxy)methyl]oxirane (8.9 g, 43.14 mmol). Thereaction mixture was stirred at 90° C. for 15 h (sometimes the reactionis complete within 2-3 hours). The reaction mixture was cooled to roomtemperature the solvent was removed under reduced pressure. The crudeproduct was purified by flash column chromatography (SiO₂, 10% EtOAc indichloromethane to 50% EtOAc in dichloromethane) to give the desiredproduct as a purple solid (8.1 g, 49%). M.p.=155-157° C.; 400 MHz ¹H NMR(CDCl₃) δ: 8.1-8.03 (m, 1H), 7.8-7.74 (m, 1H), 7.7-7.6 (m, 1H),7.55-7.45 (m, 1H), 7.35-7.28 (m, 2H), 6.9-6.8 (m, 2H), 4.10-4.17 (m,1H), 4.0-3.93 (m, 2H), 2.99-2.95 (s, 3H), 2.86-2.74 (m, 2H), 2.7-2.64(m, 2H), 2.6-2.51 (m, 1H), 2.22-2.13 (m, 2H), 1.98-1.84 (m, 2H), 1.3 (s,9H); LCMS: 508 [M+H]; enantiomeric excess determined from chiral HPLC:98%; Chiral HPLC R_(t)=50.98 min

E26.2. Synthesis of1′-[(2S)-3-(4-fluorophenoxy)-2-hydroxypropyl]-9-phenylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 225)

Compound 225 was synthesized using9-phenylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,(2S)-2-[(4-fluorophenoxy)methyl]oxirane and conditions outlined inprocedure Z. M.p.=173-175° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 8.01 (d,J=1.2 Hz, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.87 (dd, J=1.6, 7.6 Hz, 1H),7.76 (d, J=7.6 Hz, 2H), 7.57 (dd, J=7.6, 7.6 Hz, 2H), 7.52-7.47 (m, 1H),7.10 (dd, J=8.8, 8.8 Hz, 2H), 6.94 (dd, J=4.4, 8.8 Hz, 2H), 4.88 (d,J=4.8 Hz, 1H), 3.97-3.95 (m, 2H), 3.87-3.82 (m, 1H), 3.11 (s, 2H),2.87-2.78 (m, 2H), 2.54-2.39 (m, 4H), 2.03 (d, J=14.4 Hz, 2H), 1.87-1.81(m, 2H); LCMS: 546 [M+H].

E26.3. Synthesis of1′-[(2S)-3-(4-chlorophenoxy)-2-hydroxypropyl]-9-phenylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 226)

Compound 226 was synthesized using9-phenylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,(2S)-2-[(4-chlorophenoxy)methyl]oxirane and conditions outlined inprocedure Z. M.p.=93-98° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 8.01-7.97 (m,2H), 7.87 (dd, J=1.6, 7.6 Hz, 1H), 7.77 (d, J=7.2 Hz, 2H), 7.59-7.47 (m,3H), 7.31 (d, J=9.2 Hz, 2H), 6.96 (d, J=9.2 Hz, 2H), 4.90 (d, J=4.0 Hz,1H), 4.04-3.90 (m, 2H), 3.90-3.84 (m, 1H), 3.11 (s, 2H), 2.88-2.72 (m,2H), 2.52-2.38 (m, 4H), 2.03 (d, J=14.0 Hz, 2H), 1.88-1.80 (m, 2H);LCMS: 562 [M+H].

E26.4. Synthesis of1′-[(2S)-3-(4-tert-butylphenoxy)-2-hydroxypropyl]-9-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 227)

Compound 227 was synthesized using9-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,(2S)-2-[(4-tert-butylphenoxy)methyl]oxathiine and conditions outlined inprocedure Z. Mp.=153-156° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 7.90 (d, J=8.8Hz, 1H), 7.28 (d, J=8.8 Hz, 2H), 7.22 (d, J=2.4 Hz, 1H), 7.11 (dd,J=2.4, 8.8 Hz, 1H), 6.85 (d, J=8.8 Hz, 2H), 4.85 (d, J=4.8 Hz, 1H),3.96-3.92 (m, 2H), 3.92 (s, 3H), 3.86-3.81 (m, 1H), 3.07 (s, 2H), 2.81(dd, J=10.8, 22 Hz, 2H), 2.54 (m, 1H), 2.45-2.39 (m, 3H), 1.98 (d,J=14.0 Hz, 2H), 1.84-1.76 (m, 2H), 1.25 (s, 9H); LCMS: 538 [M+H].

E26.5. Synthesis of1′-[(2R)-3-(4-ethylphenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 228)

Compound 228 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,(2R)-2-[(4-ethylphenoxy)methyl]oxirane and conditions outlined inprocedure Z. M.p.=145-147° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 7.90 (d,J=7.6 Hz, 1H), 7.81-7.76 (m, 2H), 7.59-7.54 (m, 1H), 7.10 (d, J=8.4 Hz,2H), 6.87-6.82 (m, 2H), 4.85 (d, J=4.8 Hz, 1H), 3.99-3.92 (m, 2H),3.86-3.81 (m, 1H), 3.07 (s, 2H), 2.85-2.75 (m, 2H), 2.55-2.41 (m, 6H),1.98 (d, J=14.4 Hz, 2H), 1.85-1.77 (m, 2H), 1.14 (t, J=8.0 Hz, 3H);LCMS: 480 [M+H].

Example 27 Procedure AA

E27.1. Synthesis of1′-pyrazin-2-ylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 229)

A mixture ofspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (0.150 g,0.50 mmol), 2-chloropyrazine (0.57 g, 1.67 mmol), triethylamine (0.1mil, 0.72 mmol), and DMSO (50 ml) was stirred for three hours at 100° C.The crude reaction mixture was purified directly by reverse phase HPLCto give the product as a purple solid (0.014 g, 0.7%) MP=255-256° C.;400 MHz ¹H NMR (DMSO-d₆) δ: 8.41 (s, 1H), 8.10-8.07 (m, 1H), 7.91-7.81(m, 3H), 7.76-7.70 (m, 1H), 7.58-7.52 (m, 1H), 4.28-4.22 (m, 2H),3.39-3.28 (m, 2H), 3.12 (s, 2H), 2.11-2.04 (m, 2H), 1.88-1.79 (m, 2H);LCMS: 380 [M+H].

E27.2. Synthesis of1′-(6-chloropyrimidin-4-yl)spiro[naphtho[2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 230)

Compound 230 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,4,6-dichloropyrimidine and conditions outlined in procedure AA.M.p.=172-174° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 8.25 (s, 1H), 7.91-7.86(m, 2H), 7.76-7.70 (m, 1H), 7.58-7.53 (m, 1H), 7.08 (s, 1H), 3.42-3.33(m, 4H), 3.10 (s, 2H), 2.09-2.04 (m, 2H), 1.85-1.76 (m, 2H); LCMS: 414[M+H].

Example 28 Procedure AB

E28.1. Synthesis of2-[(5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1.2-b][1,4]oxathiine-2,4′-piperidin]-1′-yl)carbonyl]cyclohexanecarboxylicacid (Compound 231)

A mixture ofspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (0.5 g,1.66 mmol), hexahydro-2-benzofuran-1,3-dione (0.256 g, 1.66 mmol), andanhydrous acetonitrile (10 ml) was stirred for three hours at 80° C. Thesolvents were removed under vacuum and the crude product was purified byflash column chromatography (SiO₂, 20% EtOAc in DCM to 20% EtOAC and 2%MeOH in DCM) to afford the product as a purple solid (0.246 g, 33%).M.p.=214-220° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 11.87 (s, 1H), 7.90-7.78(m, 2H), 7.77-7.71 (m, 1H), 7.58-7.52 (m, 1H), 4.25-4.10 (m, 1H),3.90-3.75 (m, 1H), 3.50-3.37 (m, 1H), 3.37-3.23 (m, 1H), 3.15-2.90 (m,3H), 2.45-2.36 (m, 1H), 2.18-1.95 (m, 2H), 1.9-1.6 (m, 4H), 1.60-1.47(m, 2H), 1.47-1.35 (m, 2H), 1.35-1.17 (m, 2H); LCMS: 456 [M+H].

Example 29 Procedure AC E29.1. Synthesis of1′-acetylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 232)

A mixture ofspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (0.5 g,1.66 mmol), acetyl chloride (0.118 ml, 1.67 mmol), triethylamine (1.2ml, 8.61 mmol), and dichloromethane (50 ml) was stirred for three hoursat room temperature. The reaction mixture was washed with 50 ml water.The organic extract was dried with Na₂SO₄ and concentrated under reducedpressure. The crude product was purified by flash column chromatography(SiO₂, 5% EtOAc in dichloromethane) to afford the product as a purplesolid (0.327 g, 57%). M.p.=252-255° C.; 400 MHz ¹H NMR (CDCl₃) δ:8.09-8.06 (m, 1H), 7.75-7.72 (m, 1H), 7.69-7.64 (m, 1H), 7.54-7.48 (m,1H), 4.59-4.52 (m, 1H), 3.82-3.68 (m, 1H), 3.55-3.46 (m, 1H), 3.22-3.12(m, 1H), 3.0-2.91 (m, 2H), 2.26-2.18 (m, 2H), 2.18 (s, 3H), 1.82-1.72(m, 2H); LCMS: 344 [M+H].

E29.2. Synthesis of1′-isonicotinoylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 57)

Compound 57 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,isonicotinoyl chloride and conditions outlined in procedure AC.M.p.=267-269° C.; 400 MHz ¹H NMR (CDCl₃) δ: 8.74-8.70 (m, 2H), 8.06-8.10(m, 1H), 7.73-7.76 (m, 1H), 7.66-7.70 (m, 1H), 7.49-7.55 (m, 1H),7.30-7.33 (m, 2H), 4.65-4.71 (m, 1H), 3.62-3.69 (m, 1H), 3.45-3.56 (m,1H), 3.34-3.45 (m, 1H), 2.96-3.04 (m, 2H), 2.26-2.32 (m, 1H), 2.12-2.18(m, 1H), 1.85-1.97 (m, 1H), 1.68-1.78 (m, 1H); LCMS: 407 [M+H].

Example 30 Procedure AD

E30.1. Synthesis of4-(5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidin]-1′-yl)-4-oxobutanoicacid (Compound 233)

A mixture ofspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (0.5 g,1.66 mmol) and dihydrofuran-2,5-dione (0.167 ml, 1.67 mmol) andanhydrous DMSO (8 ml) was stirred for three hours at 80° C. To thereaction mixture was then added water (50 mL) and extracted withdichloromethane (2×50 mL). The organic extract was dried with sodiumsulfate and concentrated under reduced pressure. The crude product waspurified by flash column chromatography (SiO₂, 70% EtOAc in hexanes) toafford the product as a purple solid (0.057 g, 8.6%). M.p.=215-217° C.;400 MHz ¹H NMR (DMSO-d₆) δ: 12.02 (s, 1H), 7.90-7.87 (m, 1H), 7.85-7.82(m, 1H), 7.76-7.71 (m, 1H), 7.58-7.53 (m, 1H), 4.25-4.20 (m, 1H),3.87-3.81 (m, 1H), 3.44-3.36 (m, 1H), 3.10-3.00 (m, 3H), 2.60-2.55 (m,2H), 2.45-2.41 (m, 2H), 2.07-1.96 (m, 2H), 1.84-1.77 (m, 1H), 1.70-1.61(m, 1H); LCMS: 402 [M+H].

E30.2. Synthesis of{[2-(5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-yl)-2-oxoethyl]thio}aceticacid (Compound 234)

Compound 234 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,1,4-oxathiane-2,6-dione and conditions outlined in procedure AD. LCMS:434 [M+H]; R_(t)=0.98 min.

E30.3. Synthesis of2-[(5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidin]-1′-yl)carbonyl]cyclobutanecarboxylicacid (Compound 235)

Compound 235 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,3-oxabicyclo[3.2.0]heptane-2,4-dione and conditions outlined inprocedure AD. LCMS: 428 [M+H]; R_(t)=0.97 min.

E30.4. Synthesis of3-[(5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidin]-1′-yl)carbonyl]pyrazine-2-carboxylicacid (Compound 236)

Compound 236 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,furo[3,4-b]pyrazine-5,7-dione and conditions outlined in procedure AD.LCMS: 452 [M+H]; R_(t)=0.90 min.

E30.5. Synthesis of3-[(5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidin]-1′-yl)carbonyl]isonicotinicacid (Compound 237)

Compound 237 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,furo[3,4-c]pyridine-1,3-dione and conditions outlined in procedure AD.LCMS: 451 [M+H]; R_(t)=0.89 min.

Example 31 General Procedure AE

E31.1. Synthesis ofN-[(4-chlorophenyl)sulfonyl]-5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxamide(Compound 238)

To a solution ofspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (0.3 g,1.0 mmol) in dichloromethane (5 mL) was added 4-chlorobenzenesulfonylisocyanate (0.217 g, 1.0 mmol). The reaction mixture was allowed to stirat room temperature for 2 hours. The reaction was quenched by addingwater (5 mL), the organic layer was separated, dried with sodium sulfateand concentrated under reduced pressure. Flash column chromatography(SiO₂, 80% EtOAc in hexanes to 100% EtOAc) gave the desired product(0.081 g, 16%) as purple solid. M.p.=173-180° C.; (DMSO-d₆) δ 11.19 (s,1H), 7.93-7.87 (m, 3H), 7.85-7.8 (m, 1H), 7.79-7.63 (m, 3H), 7.6-7.53(m, 1H), 3.95-3.8 (m, 2H), 3.25-3.1 (m, 2H), 3.09 (s, 2H), 2.05-1.93 (m,2H), 1.8-1.63 (m, 2H); LCMS=519 [M+H].

E31.2. Synthesis ofN-[(4-fluorophenyl)sulfonyl]-5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxamide(Compound 239)

Compound 239 was synthesized usingspiro[naphtho[1,2-b)][1,4]oxathiine-2,4′-piperidine]-5,6-dione,4-fluorobenzenesulfonyl isocyanate and conditions outlined in procedureAE. M.p.=173-180° C.; (DMSO-d) δ 11.13 (s, 1H), 8.03-7.94 (m, 2H),7.92-7.87 (m, 1H), 7.85-7.8 (m, 1H), 7.77-7.7 (m, 1H), 7.6-7.52 (m, 1H),7.48-7.4 (m, 2H), 3.93-3.8 (m, 2H), 3.3-3.1 (m, 2H), 3.09 (s, 2H),2.1-1.95 (m, 2H), 1.8-1.63 (m, 2H); LCMS=503 [M+H].

E31.3: Synthesis of5,6-dioxo-N-(phenylsulfonyl)-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxamide(Compound 240)

Compound 240 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,benzenesulfonyl isocyanate and conditions outlined in procedure AE.M.p.=155-165° C., (DMSO-d₆) δ 11.09 (s, 1H), 7.93-7.88 (m, 2H),7.85-7.81 (m, 1H), 7.76-7.71 (m, 1H), 7.7-7.53 (m, 5H), 3.93-3.8 (m,2H), 3.3-3.1 (m, 2H), 3.09 (s 2H), 2.1-1.97 (m, 2H), 1.8-1.63 (m, 2H);LCMS=485 [M+H].

E31.4. Synthesis ofN-[(4-methylphenyl)sulfonyl]-5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxamide(Compound 241)

Compound 241 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,4-methylbenzenesulfonyl isocyanate and conditions outlined in procedureAE. M.p.=153-158° C., (DMSO-d₆) δ 10.99 (s, 1H), 7.92-7.87 (m, 1H),7.84-7.7 (m, 4H), 7.59-7.54 (m, 1H), 7.42-7.36 (m, 2H), 3.93-3.8 (m,2H), 3.3-3.1 (m, 2H), 3.09 (s, 2H), 2.39 (s, 3H), 2.05-1.97 (m, 2H),1.8-1.63 (m, 2H); LCMS=499 [M+H].

Example 32 General Procedure AF

E32.1. Synthesis of tert-butyl5,6-dioxo-9-phenyl-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylate(Compound 242)

To a solution of tert-butyl9-bromo-5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylate(0.05 g, 0.104 mmol) and phenylboronic acid (2 eq.) in toluene (2.0 mL)and ethanol (2.0 mL) was added saturated sodium bicarbonate solution(2.0 mL) followed by of Pd(PPh₃)₄ (0.012 g, 0.01 mmol) under N₂. Thereaction mixture was stirred at 90° C. for 3 h under an atmosphere ofnitrogen. The reaction was then allowed to cool to room temperature. Itwas then extracted with ethyl acetate (3×50 mL). The combined organicextracts were dried over Na₂SO₄ and concentrated under reduced pressure.The crude product was purified by flash column chromatography (SiO₂, 10%ethyl acetate in hexanes to 40% ethyl acetate in hexanes) to afford theproduct as purple solid (0.047 g, 94%). M.p.=102-106° C.; 400 MHz ¹H NMR(DMSO-d₆) δ: 8.03-7.97 (m, 2H), 7.86 (dd, J=2.0, 7.6 Hz, 1H), 7.79-7.77(m, 2H), 7.58-7.47 (m, 3H), 3.83 (d, J=13.6 Hz, 2H), 3.22 (br, 2H), 3.14(s, 2H), 2.04 (d, J=13.6 Hz, 2H), 1.76 (ddd, J=2.8, 12.8, 12.8 Hz, 2H),1.41 (s, 9H); LCMS: 478 [M+H].

E32.2. Synthesis of tert-butyl5,6-dioxo-9-[4-(trifluoromethyl)phenyl]-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylate(Compound 243)

Compound 243 was synthesized by using tert-butyl9-bromo-5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylate,[4-(trifluoromethyl)phenyl]boronic acid and conditions as described ingeneral procedure AF. M.p.=238-240° C.; 400 MHz ¹H NMR (DMSO-d₆) δ:8.01-7.97 (m, 4H), 7.92-7.88 (m, 3H), 3.80 (d, J=13.6 Hz, 2H), 3.23 (br,2H), 3.12 (s, 2H), 2.01 (d, J=14.0 Hz, 2H), 1.78-1.70 (m, 2H), 1.39 (s,9H); LCMS: 546 [M+H].

E32.3. Synthesis of tert-butyl5,6-dioxo-9-[3-(trifluoromethyl)phenyl]-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylate(Compound 244)

Compound 244 was synthesized by using tert-butyl9-bromo-5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylate,[3-(trifluoromethyl)phenyl]boronic acid and conditions as described ingeneral procedure AF. M.p.=231-233° C.; 400 MHz ¹H NMR (DMSO-d₆):8.10-7.92 (m, 5H), 7.86-7.76 (m, 2H), 3.80 (d, J=14.0 Hz, 2H), 3.22 (br,2H), 3.12 (s, 2H), 2.02 (d, J=14.0 Hz, 2H), 1.74 (m, 2H), 1.39 (s, 9H);LCMS: 546 [M+H].

E32.4. Synthesis of tert-butyl5,6-dioxo-9-[2-(trifluoromethyl)phenyl]-5,6-dihydro-1H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylate(Compound 245)

Compound 245 was synthesized by using tert-butyl9-bromo-5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylate,[2-(trifluoromethyl)phenyl]boronic acid and conditions as described ingeneral procedure AF. M.p.=223-225° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 7.99(d, J=7.6 Hz, 1H), 7.91 (d, J=7.2 Hz, 1H), 7.83-7.77 (t, J=7.6 Hz, 1H),7.73-7.68 (m, 2H), 7.54 (dd, J=1.6, 8.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H),3.82 (d, J=12.4 Hz, 2H), 3.11 (s, 2H), 3.04 (br, 2H), 1.97 (d, J=13.2Hz, 2H), 1.70 (ddd, J=4.8, 13.6 Hz, 2H), 1.39 (s, 9H); LCMS: 546 [M+H].

E32.5. Synthesis of tert-butyl5,6-dioxo-9-pyridin-3-yl-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylate(Compound 246)

Compound 246 was synthesized by using tert-butyl9-bromo-5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylate,pyridin-3-ylboronic acid and conditions as described in generalprocedure AF. M.p.=217-219° C.; 400 MHz ¹H NMR (CDCl₃) δ: 8.90 (d, J=2.0Hz, 1H), 8.72 (dd, J=1.6, 4.8 Hz, 1H), 8.17 (d, J=7.6 Hz, 1H), 7.95-7.91(m, 2H), 7.70 (dd, J=2.0, 8.0 Hz, 1H), 7.47 (ddd, J=0.8, 5.2, 7.6 Hz,1H), 4.01 (br, 2H), 3.25 (dd, J=12.0, 12.0 Hz, 2H), 2.97 (s, 2H), 2.14(d, J=13.2 Hz, 2H), 1.79 (m, 2H), 1.48 (s, 9H); LCMS: 479 [M+H].

E32.6. Synthesis of tert-butyl5,6-dioxo-9-pyridin-4-yl-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylate(Compound 247)

Compound 247 was synthesized by using tert-butyl9-bromo-5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylate,pyridin-4-ylboronic acid and conditions as described in generalprocedure AF. M.p.=225-227° C.; 400 MHz ¹H NMR (CDCl₃) δ: 8.79-8.77 (m,2H), 8.17 (d, J=7.6 Hz, 1H), 7.95 (d, J=1.6 Hz, 1H), 7.73 (dd, J=1.6,7.6 Hz, 1H), 7.54-7.52 (m, 2H), 4.02 (br, 2H), 3.27 (ddd, J=2.8, 11.2,12.4 Hz, 2H), 2.98 (s, 2H), 2.15 (d, J=12.8 Hz, 2H), 1.80 (m, 2H), 1.48(s, 9H); LCMS: 479 [M+H].

Example 33 General Procedure AG

E33.1. Synthesis of tert-butyl5,6-dioxo-9-piperidin-1-yl-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylate(Compound 248)

To a solution of tert-butyl9-bromo-5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylate(0.045 g, 0.09 mmol) in dioxane (2 mL) was added piperidine (0.011 g,0.15 mmol), cesium carbonate (0.045 g, 0.135 mmol, 1.5 eq) andbis(tri-tert-butyl phosphine)palladium(0) (0.010 g). The reactionmixture was stirred and heated at 115° C. for 3.5 hours. The solvent wasthen removed under reduced pressure and the residue was dissolved indichloromethane and filtered. The filtrate was concentrated underreduced pressure and the crude product purified by flash columnchromatography (SiO₂, 70% EtOAc in hexanes) to afford the product (0.020g, 45%). as a purple solid. M.p.=243-244° C.; 400 MHz ¹H NMR (DMSO-d₆)δ: 7.71 (d, J=8 Hz, 1H), 7.12 (brs, 1H), 6.94 (dd, J=2.4 and 8.8 Hz,1H), 3.78 (brd, 2H), 3.50 (s, 2H), 3.12 (brm, 4H), 3.08 (s, 2H), 2.0 (d,J=8.8 Hz, 2H), 1.56-1.73 (m, 8H), 1.39 (s, 9H); LCMS: 485 [M+H].

E33.2. Synthesis of tert-butyl9-morpholin-4-yl-5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylate(Compound 249)

Compound 249 was synthesized using tert-butyl9-bromo-5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylate,morpholine and conditions outlined in general procedure AG.M.p.=243-244° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 7.7 (d, J=8.8 Hz, 1H),7.13 (s, 1H), 6.98 (d, J=8.4 Hz, 1H), 3.73 (br, 8H), 3.40 (s, 2H), 3.12(brm, 2H), 3.08 (s, 2H), 2.0 (d, J=11.2 Hz, 2H), 1.70 (t, J=10 Hz, 2H),1.39 (s, 9H); LCMS: 487 [M+H].

Example 34 Procedure AH E34.1. Synthesis of4-{[(2S)-3-(5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-yl)-2-hydroxypropyl]oxy}benzoicacid (Compound 250)

To a solution of benzyl4-{[(2S)-3-(5,6-dioxo-5,6-dihydro-1′H-spiro-[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-yl)-2-hydroxypropyl]oxy}benzoate(0.1 g, 0.17 mmole) in EtOAc (10 mL) was added the 10% Pd on carbon(0.020 g). The reaction mixture was subjected to an atmospheric pressureof hydrogen for three days. The mixture was filtered over Celite andconcentrated under reduced pressure affording the title compound as adeep purple solid. M.p.=173-175° C.; 400 MHz ¹H NMR (DMSO-d₆) δ:7.92-7.86 (m, 3H), 7.83-7.76 (m, 2H), 7.60-7.54 (m, 1H), 7.03 (d, J=8.6Hz, 2H), 4.12-3.92 (m, 4H), 3.08 (s, 2H), 2.90-2.74 (m, 2H), 2.60-2.40(m, 3H), 2.35-1.94 (m, 2H), 1.88-1.76 (m, 2H); LCMS: 496 [M+H].

Example 35 Procedure AI

E35.1. Synthesis(1S)-2-(4-tert-butylphenoxy)-1-[(5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidin]-1′-yl)methyl]ethylacetate (Compound 251)

To a solution of1′-[(2S)-3-(4-tert-butylphenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(0.5 g, 0.99 mmol) in dichloromethane (10 mL), which had been cooled to0° C. was added dimethylaminopyridine (0.012 g, 0.099 mmol) followed byacetic anhydride (0.19 mL, 1.97 mmol). The reaction was stirred at 0° C.for 8 hours. The reaction mixture was washed with saturated NaHCO₃ (20mL), dried with sodium sulfate and concentrated under reduced pressure.The crude product was purified by flash column chromatography (SiO₂, 30%EtOAc in hexanes) to afford the product (0.53 g, 97%) as a purple solid.M.p.=64-66° C.; 400 MHz ¹H NMR (CDCl₃) δ 8.05-7.95 (m, 1H), 7.78-7.7 (m,1H), 7.68-7.6 (m, 1H), 7.5-7.4 (m, 1H), 7.3-7.22 (m, 2H), 6.87-6.8 (m,2H), 5.38-5.25 (m, 1H), 4.18-4.03 (m, 3H), 2.89 (s, 2H), 2.9-2.8 (m,2H), 2.78-2.7 (m, 2H), 2.65-2.52 (m, 2H), 2.06 (s, 3H), 2.15-2.02 (m,2H), 1.86-1.75 (m, 2H), 1.28 (s, 9H); LCMS: 550 [M+H].

Example 36 Procedure AJ

E36.1. Synthesis of(1S)-2-(4-tert-butylphenoxy)-1-[(5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-yl)methyl]ethylN-(tert-butoxycarbonyl)glycinate (Compound 252)

To a solution of1′-[(2S)-3-(4-tert-butylphenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dionehydrochloride (1.0 g, 1.84 mmol) in dimethylformamide (10 mL) was addedN-(tert-butoxycarbonyl)glycine (0.415 g, 2.39 mmol) and triethylamine(0.52 mL, 3.86 mmol) followed by HBTU (0.782 mmol, 2.39 mmol). Thereaction mixture was stirred at room temperature for 16 hours. Thereaction was then diluted with EtOAc (100 mL) and washed with saturatedNaHCO₃ (2×50 mL), brine (3×50 mL), dried with sodium sulfate andconcentrated under reduced pressure. The crude product was purified byflash column chromatography (SiO₂, 30% EtOAc in hexanes to 50% EtOAc inhexanes) to afford the product (0.53 g, 97%) as a purple solid.M.p.=85-95° C.; 400 MHz ¹H NMR (CDCl₃) δ 8.05-7.95 (m, 1H), 7.78-7.7 (m,1H), 7.68-7.6 (m, 1H), 7.5-7.4 (m, 1H), 7.3-7.22 (m, 2H), 6.87-6.8 (m,2H), 5.5-5.4 (m, 1H), 5.08-5.0 (m, 1H), 4.2-4.1 (m, 1H), 4.0-3.78 (m,2H), 3.0-2.86 (m, 3H), 2.85-2.8 (m, 2H), 2.79 (s, 2H), 2.76-2.58 (m,2H), 2.15-2.02 (m, 2H), 1.94-1.80 (m, 2H), 1.44 (s, 9H), 1.28 (s, 9H);LCMS: 665 [M+H].

Example 37 Procedure AK E37.1. Synthesis of(1S)-2-(4-tert-butylphenoxy)-1-[(5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-yl)methyl]ethylglycinate hydrochloride (Compound 253)

To a solution of(1S)-2-(4-tert-butylphenoxy)-1-[(5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-yl)methyl]ethylN-(tert-butoxycarbonyl)glycinate (0.2 g, 0.3 mmol) in isopropyl acetate(50 mL) was added 12.1N HCl (3.4 mL). The reaction was stirredvigorously for 16 hours after which a purple solid separated out. Thesolid was filtered and washed with isopropyl acetate (50 mL). The solidwas then dried under high vacuum to afford the product (0.143 g, 62%) asa purple solid. M.p.=193-195° C.; 400 MHz ¹H NMR (DMSO-d₆) δ 11.45-11.25(br m, 1H), 8.47 (brs, 3H), 7.98-7.9 (m, 2H), 7.8-7.7 (m, 1H), 7.63-7.55(m, 1H), 7.45-7.28 (m, 2H), 6.94-6.87 (m, 2H), 5.8-5.7 (brs, 1H),4.3-4.15 (m, 3H), 4.0-3.2 (m, 7H), 3.1 (s, 2H), 2.45-2.2 (m, 4H), 1.25(s, 9H); LCMS: 565 [M+H]

Example 38 Procedure AL E38.1. Synthesis of5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboximidamidiniumchloride (Compound 254)

To a solution ofspiro[naphtha[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (0.500 g,1.66 mmol) in dimethylformamide (10 mL) was treated with pyrazolecarboxamide hydrochloride (0.243 g, 1.66 mmol) and diisopropylethylamine(0.289 mL, 1.66 mmol). The reaction was heated at 60° C. for 6 hours,then cooled to room temperature. The reaction mixture was diluted withether (100 mL) and vigorously stirred for one hour. The supernatant wasdecanted, more ether was added. This process was repeated until a solidwas formed. The solid was collected, washed with ether, and dried underhigh vacuum to give a purple solid (0.503 g, 88%). M.p.=262-264° C.; 400MHz ¹H NMR (DMSO-d₆) δ: 7.87 (m, 2H), 7.73 (t, J=7.6 Hz, 1H), 7.67 (br.s, 3H), 7.56 (t, 1H), 3.87 (d, J=13.6 Hz, 2H), 3.38 (m, 2H), 3.34 (s,2H), 2.06 (d, J=13.6 Hz, 2H), 1.85 (m, 2H); LCMS: 344 [M+H].

Example 39 Procedure AM

E39.1. Synthesis of di-tert-butyl[(E)-(5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-yl)methylylidene]biscarbamate(Compound 255)

To a solution ofspiro[naphtha[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (2.60 g,8.63 mmol), N¹,N²-bis(tert-butoxycarbonyl)-S-methylisothiourea (2.76 g,9.49 mmol), and triethylamine (3.60 mL, 25.88 mmol) in anhydrousdimethylformamide was added mercury (II) chloride (2.58 g, 9.49 mmol).The suspension was stirred at room temperature for 4 hours and thenconcentrated under reduced pressure. The crude reaction mixture wassuspended in diethylether (200 mL) and filtered. The filtrate was washedwith saturated aqueous ammonium chloride (50 mL), water (50 mL), brine(50 mL), dried over sodium sulfate and concentrated under reducedpressure. The crude product was purified by flash column chromatography(SiO₂, 10% Methanol in dichloromethane) to afford the product as apurple solid (4.10 g, 87%). M.p.=272-274° C.; 400 MHz ¹H NMR (CDCl₃) δ:10.30 (br. s, 1H), 8.06 (m, 1H), 7.73 (m, 1H), 7.64 (m, 1H), 7.50 (m,1H), 4.11 (m, 2H), 3.39-3.44 (m, 2H), 2.96 9 (s, 2H), 2.18 (d, J=12.8Hz, 2H), 2.00-1.95 (m, 2H), 1.50 (br. s, 18H); LCMS: 544 [M+H].

Example 40 Procedure AN

E40.1. Synthesis ofN-benzyl-5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboximidamidiniumchloride (Compound 256)

Step (i): To a solution of di-tert-butyl[(E)-(5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidin]-1′-yl)methylylidene]biscarbamate(0.090 g, 0.166 mmol), in toluene (2 mL) was added tetrabutylammoniumiodide (0.006 g, 0.033 mmol), potassium hydroxide (0.019 mg, 0.332 mmol)and water (2 mL) followed by benzyl bromide (0.039 mL, 0.332 mmol). Thereaction mixture was stirred at 50° C. for 3 hours, then poured intowater (20 mL) and extracted with dichloromethane (3×50 mL). The combinedorganic extracts were washed with brine (30 mL), dried over sodiumsulfate, and concentrated under reduced pressure to afford the desiredintermediate, which was used in step (ii) without any furtherpurification.

Step (ii): To a solution of the crude intermediate from step (i) intoluene was added a solution of 4.0 M HCl (g) in dioxane (0.166 mL,0.664 mmol). The reaction mixture was allowed to stir at roomtemperature for 3 hours, and then concentrated to dryness under reducedpressure. The crude product was washed with ether and dried under highvacuum to afford the product as a purple solid (0.039 g, 54%).M.p.=190-195° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 8.42-8.30 (m, 1H),7.90-7.83 (m, 3H), 7:74 (t, J=7.2 Hz, 1H)), 7.56 (t, J=7.6 Hz, 1H)),7.39-7.27 (m, 5H), 4.48-4.46 (m, 2H), 3.90 (d, J=14 Hz, 2H), 3.40-3.37(m, 4H), 2.06 (d, J=14 Hz, 2H), 1.90-1.86 (m, 2H); LCMS: 434 [M+H].

Example 41 Procedure AO

E41.1. Synthesis of tert-butyl4-(5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-yl)piperidine-1-carboxylate(Compound 257)

To a solution ofspiro[naphtho[12-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (5.0 g,16.61 mmol), tert-butyl 4-bromopiperidine-1-carboxylate (20.7 g, 80mmol) and cesium carbonate (10.8 g, 33.2 mmol) in dimethylformamide (50mL) was heated at 90° C. for 30 hours. The resulting mixture was dilutedwith dichloromethane (200 mL), washed with water (3×50 mL), dried oversodium sulfate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography (SiO₂, 5% CH₃OH in CH₂Cl₂)to afford the product as a purple solid (1.1 g, 14%). M.p.=87-91° C.;400 MHz ¹H NMR (CDCl₃) δ: 8.03 (d, J=7.2 Hz, 1H), 7.72 (d, J=7.6 Hz,1H), 7:65 (t, J=8.0 Hz, 1H), 7.47 (t, J=8.0 Hz, 1H), 4.17 (brs, 2H),2.91 (s, 2H), 2.85 (m, 2H), 2.63-2.69 (m, 4H), 2.52 (m, 1H), 2.15 (d,J=13.2 Hz, 2H), 1.88-1.80 (m, 6H), 1.47 (s, 9H); LCMS: 484 [M+H].

E41.2. Synthesis of1′-cyclohexylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 258)

Compound 258 was synthesized usingspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,iodocyclohexane, and conditions outlined in procedure AO. M.p.=195-196°C.; 300 MHz ¹H NMR (DMSO-d) δ: 7.89 (d, J=7.2 Hz, 1H), 7.77-7.75 (m,2H), 7.58-7.52 (m, 1H), 2.77-2.72 (m, 2H), 2.64-2.58 (m, 2H), 2.34 (br.s, 1H), 2.01 (d, J=17.6 Hz, 2H), 1.83-1.75 (m, 6H), 1.57 (d, J=14.8 Hz,2H), 1.30-1.15 (m, 6H); LSMS: 384 [M+H].

Example 42 Procedure AP

E42.1. Synthesis of1′-(3,4-dioxo-3,4-dihydronaphthalen-1-yl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione(Compound 259)

To a solution ofspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (2.3 g,7.64 mmol) in dichloromethane (200 mL) was added naphthalene-1,2-dione(1.2 g, 7.64 mmol) followed by triethylamine (1.05 mL, 8.4 mmol). Thereaction mixture was stirred at room temperature for 2 hours. Themixture was then concentrated under reduced pressure. The residue wasdissolved in minimal tetrahydrofuran and then precipitated with EtOAc.The precipitate was collected by vacuum filtration. The filtrate wasthen suspended in tetrahydrofuran:EtOAc (1:1, 100 mL). The suspensionwas stirred, sonicated, and the solid collected by vacuum filtration.The tituration was once more repeated and the resulting reddish brownpowder was recrystallized from dichloromethane/methanol (1:1) to affordthe product (0.5 g) as the pure reddish brown solid. M.p.=250-260° C.;400 MHz ¹H NMR (DMSO-d₆) δ: 7.89-7.93 (m, 3H), 7.71-7.81 (m. 3H),7.55-7.65 (m, 2H), 6.10 (s, 1H), 3.67-3.75 (m, 2H), 3.45-3.53 (m, 2H),3.19 (s, 2H), 2.20 (m, 2H), 1.25 (m, 1H), 1.01 (m, 1H). LCMS: 458 [M+H].

Example 43 Procedure AQ E43.1. Synthesis of4-hydroxyspiro[cyclohexane-1,2′-naphtho[1,2-b][1,4]oxathiine]-5′,6′-dione(Compound 260)

To a solution of4H-spiro[cyclohexane-1,2′-naphtho[1,2-b][1,4]oxathiine]-4,5′,6′-trione(0.180 g, 0.57 mmol) in anhydrous methanol (25 ml) was added sodiumborohydride (0.085 mg, 2.25 mmol). On addition the reaction mixtureturned pale yellow, which after 30 minutes turned back to purple. Thereaction mixture was stirred at room temperature for 16 hours afterwhich the solvent was removed under reduced pressure. The residue wasdissolved in dichloromethane (50 ml) and water (50 ml) was added to it.The organic layer was removed and the aqueous layer was extracted withdichloromethane (3×50 ml). The combined organic extracts were dried oversodium sulfate, filtered and concentrated under reduced pressure. Thecrude product was purified by C-18 reverse phase preparative liquidchromatography to afford the product (0.018 g) as a purple solid.M.p.=166-168° C., 400 MHz ¹H NMR (acetone-d₆) δ: 7.97 (dd, 1H), 7.90(dd, 1H), 7.80 (dt, 1H), 7.59 (dt, 1H), 3.74 (m, 1H), 3.06 (s, 2H), 2.21(m, 2H), 1.89 (m, 2H), 1.74 (m, 4H); LCMS: 317 [M+H].

Example 44 E44.1. Synthesis ofspiro[cyclohexane-1,2′-naphtho[1,2-b][1,4]oxathiine]-5′,6′-dione(Compound 261)

Step (i): 1-(mercaptomethyl)cyclohexanol was synthesized using1-oxaspiro[2.5]octane as outlined in procedure C.

Step (ii): The crude 1-(mercaptomethyl)cyclohexanol was then reactedwith naphthalene-1,2-dione as outlined in procedure F [both step (i) and(ii)] to afford crudespiro[cyclohexane-1,2′-naphtho[1,2-b][1,4]oxathiine]-5′,6′-dione. Thecrude spiro[cyclohexane-1,2′-naphtho[1,2-b][1,4]oxathiine]-5′,6′-dionewas purified by flash column chromatography (SiO₂, 100% dichloromethane)to afford the product (0.183 g) as a purple solid. M.p.=194-195° C., 400MHz ¹H NMR CDCl₃ δ 8.05-8.0 (m, 1H), 7.8-7.72 (m, 1H), 7.68-7.6 (m, 1H),7.5-7.4 (m, 1H), 2.91 (s, 2H), 2.15-2.0 (m, 2H), 1.8-1.53 (m, 7H),1.5-1.35 (m, 1H); LCMS=301 [M+H].

E44.2. Synthesis of2′,3′,5′,6′-tetrahydrospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-pyran]-5,6-dione(Compound 262)

Step (i): 1,6-dioxaspiro[2.5]octane was synthesized usingtetrahydro-4H-pyran-4-one as outlined in procedure A.

Step (ii): The crude 1,6-dioxaspiro[2.5]octane was then used tosynthesize 4-(mercaptomethyl)tetrahydro-2H-pyran-4-ol as outlined inprocedure B.

Step (iii): The crude 4-(mercaptomethyl)tetrahydro-2H-pyran-4-ol wasthen reacted with naphthalene-1,2-dione as outlined in procedure F [bothstep (i) and (ii)] to afford crude2′,3′,5′,6′-tetrahydrospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-pyran]-5,6-dione.The crude2′,3′,5′,6′-tetrahydrospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-pyran]-5,6-dionewas purified by flash column chromatography (SiO₂, 100% dichloromethane)to afford the product as a purple solid. M.p.=195-197° C.; 400 MHz ¹HNMR (CDCl₃) δ: 8.06 (dd, J=7.6 1.0 Hz, 1H), 7.79 (dd, J=7.6 0.8 Hz, 1H),7.67 (td, J=8.0 1.6 Hz 1H), 7.50 (td, J=8.0 1.2 Hz, 1H), 3.96-3.83 (m,4H), 2.97 (s, 2H), 2.10-2.05 (m, 2H), 1.95-1.87 (m, 2H); LCMS: 303[M+H].

E44.3. Synthesis of2′,3′,5′,6′-tetrahydrospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-thiopyran]-5,6-dione(Compound 263)

Step (i): 1-oxa-6-thiaspiro[2.5]octane was synthesized usingtetrahydro-4H-thiopyran-4-one as outlined in procedure A.

Step (ii): The crude 1-oxa-6-thiaspiro[2.5]octane was then used tosynthesize 4-(mercaptomethyl)tetrahydro-2H-thiopyran-4-ol as outlined inprocedure B.

Step (iii): The crude 4-(mercaptomethyl)tetrahydro-2H-thiopyran-4-ol wasthen reacted with naphthalene-1,2-dione as outlined in procedure F [bothstep (i) and (ii)] to afford crude2′,3′,5′,6′-tetrahydrospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-thiopyran]-5,6-dione.The crude2′,3′,5′,6′-tetrahydrospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-thiopyran]-5,6-dionewas purified by flash column chromatography (SiO₂, 25% EtOAc in hexanes)to afford the product as a purple solid. M.p.=221-223° C., 400 MHz ¹HNMR (CDCl₃) δ 8.05 (dd, d, J=7.4 Hz, 1.1 Hz, 1H), 7.78 (d, J=8.6 Hz,1H), 7.67 (dt, J=6.2 Hz, 1.1 Hz, 1H), 7.50 (dt, J=6.2 Hz, 1.1 Hz, 1H),3.10-3.03 (m, 1H), 2.64-2.60 (m2, 2H), 2.47-2.43 (m, 2H), 1.99-1.92 (m,2H); LCMS: 319 [M+H].

E44.4. Synthesis of4-phenylspiro[cyclohexane-1,2′-naphtho[1,2-b][1,4]oxathiine]-5′,6′-dione(Compound 264)

Step (i): 6-phenyl-1-oxaspiro[2.5]octane was synthesized using4-phenylcyclohexanone as outlined in procedure A.

Step (ii): The crude 6-phenyl-1-oxaspiro[2.5]octane was then used tosynthesize 1-(mercaptomethyl)-4-phenylcyclohexanol as outlined inprocedure C.

Step (iii): The crude 1-(mercaptomethyl)-4-phenylcyclohexanol was thenreacted with naphthalene-1,2-dione as outlined in procedure F [both step(i) and (ii)] to afford crude4-phenylspiro[cyclohexane-1,2′-naphtho[1,2-b][1,4]oxathiine]-5′,6′-dione.The crude4-phenylspiro[cyclohexane-1,2′-naphtho[1,2-b][1,4]oxathiine]-5′,6′-dionewas purified by flash column chromatography (SiO₂, 100% dichloromethane)to afford the product as a purple solid. M.p.=183-187° C.; 400 MHz ¹HNMR (DMSO) δ: 7.92-7.78 (m, 3H), 7.60-7.56 (td, 1H), 7.34-7.18 (m, 5H),3.09 (s, 2H), 2.71-2.66 (m, 1H), 2.20 (d, 2H), 1.90-1.72 (m, 6H); LCMS:377 [M+H].

E44.5. Synthesis ofdispiro[1,3-dioxolane-2,1′-cyclohexane-4′,2″-naphtho[1,2-b][1,4]oxathiine]-5″,6″-dione(Compound 265) and4H-spiro[cyclohexane-1,2′-naphtho[1,2-b][1,4]oxathiine]-4,5′,6′-trione(Compound 266)

Step (i): 1,7,10-trioxadispiro[2.2.4.2]dodecane was synthesized using1,4-dioxaspiro[4.5]decan-8-one as outlined in procedure A.

Step (ii): The crude 1,7,10-trioxadispiro[2.2.4.2]dodecane was then usedto synthesize 8-(mercaptomethyl)-1,4-dioxaspiro[4.5]decan-8-ol asoutlined in procedure B.

Step (iii): The crude 8-(mercaptomethyl)-1,4-dioxaspiro[4.5]decan-8-olwas then reacted with naphthalene-1,2-dione as outlined in procedure F[both step (i) and (ii)] to afford crudedispiro[1,3-dioxolane-2,1′-cyclohexane-4′,2″-naphtho[1,2-b][1,4]oxathiine]-5″,6″-dioneand4H-spiro[cyclohexane-1,2′-naphtho[1,2-b][1,4]oxathiine]-4,5′,6″-trione.The crudedispiro[1,3-dioxolane-2,1′-cyclohexane-4′,2″-naphtho[1,2-b][1,4]oxathiine]-5″,6″-dioneand4H-spiro[cyclohexane-1,2′-naphtho[1,2-b][1,4]oxathiine]-4,5′,6′-trionewas purified by flash column chromatography (SiO₂, gradient from 1%EtOAc in hexanes to 50% EtOAc in hexanes) to afford both the products asa purple solid. Compound 265: M.p.=251-252° C., 400 MHz ¹H NMR (DMSO-d₆)δ: 7.87 (dd, 1H), 7.74 (m, 2H), 7.54 (dt, 1H), 3.89 (s, 4H), 3.08 (s,2H), 2.05 (m, 2H), 1.80 (m, 4H), 1.67 (m, 2H); LCMS: 359 [M+H]. Compound266: M.p.=117-118° C., 400 MHz ¹H NMR (DMSO-d₆) δ: 7.88 (dd, 1H), 7.84(d, 1H), 7.71 (dt, 1H), 7.54 (dt, 1H), 3.16 (s, 2H), 2.63 (m, 2H), 2.31(m, 41H), 2.10 (m, 2H); LCMS: 315 [M+H].

E44.6. Synthesis of tert-butyl(5′,6′-dioxo-5′,6′-dihydrospiro[cyclohexane-1,2′-naphtho[1,2-b][1,4]oxathiin]-4-yl)carbamate(Compound 267)

Step (i): tert-butyl 1-oxaspiro[2.5]oct-6-ylcarbamate was synthesizedusing tert-butyl (4-oxocyclohexyl)carbamate as outlined in procedure A.

Step (ii): The crude tert-butyl 1-oxaspiro[2.5]oct-6-ylcarbamate wasthen used to synthesize tert-butyl[4-hydroxy-4-(mercaptomethyl)cyclohexyl]carbamate as outlined inprocedure C.

Step (iii): The crude tert-butyl[4-hydroxy-4-(mercaptomethyl)cyclohexyl]carbamate was reacted withnaphthalene-1,2-dione as outlined in procedure G [both step (i) (ii) and(iii)] to afford crude tert-butyl(5′,6′-dioxo-5′,6′-dihydrospiro[cyclohexane-1,2′-naphtho[1,2-b][1,4]oxathiin]-4-yl)carbamate.The crude product was purified by flash column chromatography (SiO₂,100% dichloromethane) to afford the product as a purple solid.M.p.=224-225° C.; 400 MHz ¹H NMR (DMSO-d₆) δ: 7.90 (dd, J=7.6 Hz, 0.8Hz, 1H), 7.83 (d, J=6.8 Hz, 1H), 7.75 (td, J=7.6 Hz, 1.2 Hz, 1H), 6.92(d, J=8.4 Hz, 1H), 3.34 (br, 1H), 3.02 (s, 2H), 2.05 (d, J=10.8 Hz, 2H),1.76-1.53 (m, 6H), 1.39 (s, 9H); LCMS: 416 [M+H].

Example 45 Antiproliferative Activity

Compounds of the present invention have demonstrated potentantiproliferative activity against a variety of cancer cell lines,including DLD-1 and HT-29 human colon carcinoma cells; A549 human lungcarcinoma cells; DU-145 human prostate carcinoma cells; K-562 humanleukemia cells; and PACA-2 human pancreatic carcinoma cells. Sinceβ-lapachone induces cell death only in cancer cell lines and not innormal cells (Li et al., (2003) Proc Natl Acad Sci USA. 100(5): 2674-8),the present compounds were also tested in a panel of normal cell linesfrom a variety of tissues including NCM-460 normal colon epithelialcells.

Table 1 shows the concentrations of the compounds required to inhibit50% of cell growth (IC₅₀). (In Table 1, “N/A”=“data not available”) Asshown in Table 1. IC₅₀ values in the low micromolar range and below wereobtained for several of these compounds in all cancer cell lines tested.

Another effect of the compounds of the present invention is theinduction or elevation of activity (e.g. elevation of the level) of oneor more checkpoint molecules (i.e., a member of the E2F family oftranscription factors). Studies have shown that β-lapachone inducesactivation of E2F1 checkpoint pathway in nuclei of cancer cells but notin normal cells, resulting in the arrest of cancer cells in G1 and/or Sphase. Several compounds of the present invention were effective inactivating the E2F1 checkpoint pathway (e.g. elevation of E2F1 levels),thus causing G1 and/or S phase arrest. Furthermore, the compounds of thepresent invention have no significant toxic effects on normal cells(See. Table 1).

Cell viability was determined by measuring the activity of dehydrogenaseenzymes in metabolically active cells using a tetrazolium compound, MTS.The assay was performed as described in Promega Technical Bulletin No.169 (CellTiter 96 Aqueous Non-Radioactive Cell Proliferation Assay): Allcells lines were grown in DMEM media (4.5 g/L glucose) supplemented with15% heat-inactivated FBS, 10 mM L-glutamine, and 10 mM HEPES. Briefly,cells were seeded in 96-well plates and incubated for 16-24 hours; testcompounds were serially diluted in DMSO, further diluted in cell culturemedia, then added to cells (final DMSO concentration of 0.33% v/v);cells were incubated in the presence of compound for 4 hours; MTS wasadded to the cells and incubated for four hours; SDS was added to afinal concentration of 1.4% v/v and absorbance at 490 nM was measuredwithin two hours using a plate reader. The amount of 490 nM absorbancewas directly proportional to the number of living cells in the culture.The IC₅₀ was defined as the concentration of compound that results in a50% reduction in the number of viable cells as compared to control wellstreated with DMSO only (0.33% v/v) and 1.4% v/v SDS, and was calculatedusing non-linear regression analysis within Activity base softwaresuite.

The assays of the present invention as shown in Table 1 and methods ofmeasuring induction of E2F1 activity and elevation of E2F1 levels can becarried out following the descriptions found in Li et al., (2003) ProcNatl Acad Sci USA. 100(5): 2674-8 and U.S. Patent ApplicationPublication No. 2002/0169135, both incorporated herein by reference.

The antiproliferative activity of the present spiro-oxathiinenaphthoquinone derivative compounds indicate that the compounds of thepresent invention may show wide anticancer activity. For example, thecompounds of the invention are effective for treating cancers such ascolon, lung, prostate, leukemia, and pancreas. These treatments areaccomplished utilizing the present spiro-oxathiine naphthoquinonederivative compounds (Formula I), alone or can be utilized incombination with, other chemotherapy agents or zenith radiation therapy.For example, the compounds of the present invention are used for theprevention or treatment of a hyperproliferative disorder and cancer(e.g. as a preventative drug) by preventing hyperproliferative or cancercell formation. The results of experiments with β-lapachone and similarchemical compounds have shown that the compounds of the presentinvention have a cell death effect on a variety of human cancer cellsand that they can inhibit growth of other human cancer cells.

Example 45 Colon Cancer Xenograft Model

Treatment with several compounds of the present invention reduced themean tumor volume of human colon cancer xenograft by 41.7˜70.2% comparedto vehicle treated control.

E45.1

Athymic female nude mice (CR-L:NU/NU-nuBR) were injected subcutaneouslyin the flank with HT29 human colon cancer cells (5×10⁶ cells/mouse).Tumors were allowed to grow to approximately 70 mm³ in size. Animalswere randomized into two groups of eight animals per group. At day fourpost injection, mice with established tumors were treatedintraperitoneally with either Compound 184 (32 mg/kg) or vehiclecontrol. Drug or vehicle was administered every Monday, Wednesday andFriday for a total of nine doses (qMWFx3). Tumor size was evaluatedperiodically during the study. For each subject, tumor volume wascalculated using the formula (L×W²)/2 where L and W were the length andwidth of the tumor, respectively. The arithmetic mean tumor volume wascalculated for each treatment group +/− standard error of the mean(SEM).

Treatment with Compound 184 at 32 mg/kg qMWF reduced the mean tumorvolume of human colon cancer xenograft by 70.2% (% T/C 29.8, p=0.02)compared to vehicle treated control. See, e.g., FIG. 1A.

E45.2

Athymic female nude mice (CRL:NU/NU-nuBR) were injected subcutaneouslyin the flank with HT29 human colon cancer cells (5×10⁶ cells/mouse).Tumors were allowed to grow to approximately 90 mm³ in size. Animalswere randomized into three groups of eight animals per group. At day sixpost injection, mice with established tumors were treatedintraperitoneally with either Compound 186 (32 mg/kg) or Compound 187(48 mg/kg) and vehicle control. Drug or vehicle was administered everyMonday, Wednesday and Friday for a total of nine doses (qMWFx3). Tumorsize was evaluated periodically during the study. For each subject,tumor volume was calculated using the formula (L×W²)/2 where L and Wwere the length and width of the tumor, respectively. The arithmeticmean tumor volume was calculated for each treatment group +/− standarderror of the mean (SEM).

Treatment with Compound 186 (32 mg/kg qMWF) and Compound 187 (48 mg/kgqMWF) reduced the mean tumor volume of human colon cancer xenograft by50% (Opt. % T/C=50% p=0.02) and 62% (Opt. % T/C=38% p=0.00006)respectively compared to vehicle treated control. See, e.g., FIG. 1B.

E45.3

Athymic female nude mice (CRL:NU/NU-nuBR) were injected subcutaneouslyin the flank with HT29 human colon cancer cells (5×10⁶ cells/mouse).Tumors were allowed to grow to approximately 60 mm³ in size. Animalswere randomized into two groups of eight animals per group. At day fivepost injection, mice with established tumors were treatedintraperitoneally with either Compound 182 (40 mg/kg) or vehiclecontrol. Drug or vehicle was administered every Monday, Wednesday andFriday for a total of nine doses (qMWFx3). Tumor size was evaluatedperiodically during the study. For each subject, tumor volume wascalculated using the formula (L×W²)/2 where L and W were the length andwidth of the tumor, respectively. The arithmetic mean tumor volume wascalculated for each treatment group +/− standard error of the mean(SEM).

Treatment with Compound 182 at 40 mg/kg qMWF reduced the mean tumorvolume of human colon cancer xenograft by 55.2% (% T/C=44.8% p=0.02)compared to vehicle treated control. See, e.g., FIG. 1C.

E45.4

Athymic female nude nmice (CRL:NU/NU-nuBR) were injected subcutaneouslyin the flank with HT29 human colon cancer cells (5×10⁶ cells/mouse).Tumors were allowed to grow to approximately 50 mm³ in size. Animalswere randomized into three groups of five animals per group. At dayeight post injection, mice with established tumors were treatedintraperitoneally with either Compound 180 (40 mg/kg) or Compound 125(40 mg/kg) and vehicle control. Drug or vehicle was administered everyMonday, Wednesday and Friday for a total of twelve doses (qMWFx4). Tumorsize was evaluated periodically during the study. For each subject,tumor volume was calculated using the formula (L×W²)/2 where L and Wwere the length and width of the tumor, respectively. The arithmeticmean tumor volume was calculated for each treatment group +/−standarderror of the mean (SEM).

Treatment with Compound 180 and Compound 125 at 40 mg/kg qMWF reducedthe mean tumor volume of human colon cancer xenograft by 41.7% (% T/C58.3) and 57.8% (% T/C 46.2) respectively compared to vehicle treatedcontrol. See, e.g., FIG. 1D.

TABLE 1 IC₅₀ Values (μM) Normal Cancerous Cells Cells Fold E2F-1Compound Lung Colon Prostate Leukemia Colon Pancreas Colon SelectivityInduction No. A549 DLD-1 DU-145 K-562 HT-29 PACA-2 NCM-460(NCM-460/DLD1) (HT-29) 13 3.78 1.46 1.54 1.35 N/A 0.856 3.25 2.2 N/A20 >100 49.5 60.5 48 N/A 27.5 61.7 1.2 N/A 39 7.69 1.45 3.86 1.87 N/A1.52 6.35 4.4 N/A 40 15.5 4.09 14.4 3.92 N/A 8.39 10.2 2.5 N/A 41 4.841.58 3.1 1.44 N/A 1.47 5.8 3.7 N/A 42 43 8.95 12.7 5.64 N/A 5.12 12.61.4 N/A 43 9.96 2.26 4.12 2.77 N/A 2.14 9.44 4.2 N/A 45 19.7 4 4.3 3.95N/A 4.49 9.84 2.5 N/A 46 >100 5.26 5.03 9.61 N/A 4.24 28.6 5.4 N/A 4811.8 1.55 4.12 1.5 N/A 2.37 5.7 3.7 N/A 49 5.58 2.87 4.11 1.8 N/A 2.397.72 2.7 N/A 50 5.41 1.54 3.55 1.44 N/A 1.42 7.14 4.6 N/A 51 >100 11.65.52 10.3 N/A 4.28 33 2.8 N/A 52 14.4 4.15 4.49 2.71 N/A 3.92 10.1 2.4N/A 53 3.83 1.42 1.37 1.44 2.21 1.06 8.52 6.0 YES 54 7.57 1.49 1.91 1.74N/A 1.33 11 7.4 N/A 55 4.57 2.1 3.85 3.93 5.74 3.36 11.2 5.3 Yes 57 24.84.29 12.2 4.37 N/A 5.36 9.91 2.3 N/A 58 42.2 13.7 12.2 14.2 N/A 11 79.95.8 N/A 59 16.8 4.1 10.4 4.24 N/A 4.24 10.7 2.6 N/A 60 8.59 2.21 4.163.38 N/A 2.39 10.5 4.8 N/A 75 19.4 4.45 7.82 2.93 N/A 4.02 9.56 2.1 N/A76 >100 27.1 28 >33.3 N/A 14.3 100 3.7 N/A 77 >100 20.6 49.2 22.9 N/A16.1 76.4 3.7 N/A 78 46.7 11.1 12.7 14.7 N/A 11.1 30 2.7 N/A 79 23.58.26 11.9 5.92 N/A 7.26 20.5 2.5 N/A 80 18.3 3.53 4.25 3.81 N/A 3.3512.9 3.7 N/A 81 >100 12.3 13.7 12.3 N/A 12.1 30.2 2.5 N/A 82 15.3 8.887.88 10 N/A 4.59 21.1 2.4 N/A 84 16.9 4.69 10.3 6.83 N/A 6.38 19.1 4.1N/A 85 6.38 1.29 1.88 1.32 N/A 1.14 3.31 2.6 N/A 86 3.84 1.48 1.03 2.17N/A 1.33 10.1 6.8 N/A 87 3.31 3.04 0.888 3.11 N/A 1.34 30.5 10.0 N/A 8813.3 1.49 4.33 2.14 N/A 1.85 6.08 4.1 N/A 90 21 1.84 4.18 1.8 N/A 1.5910.1 5.5 N/A 91 10.2 1.6 2.87 1.45 N/A 1.35 9 5.6 N/A 92 31 4.01 9.114.54 N/A 4.29 13.1 3.3 N/A 93 4.87 1.68 4.25 2.46 N/A 3.55 10.8 6.4 N/A94 8.52 2.41 3.69 2.49 N/A 2.81 9.48 3.9 N/A 95 51.4 10.9 5.13 12.3 N/A4.72 37.7 3.5 N/A 96 >100 31.7 20 36.3 20.5 26.7 100 3.2 Yes 97 26 4.396.59 4.28 12.6 4.93 13.3 3.0 YES 98 7.3 3.11 3.98 1.43 N/A 1.61 4.78 1.5N/A 100 8 1.13 1.39 1.37 N/A 1.32 5.67 5.0 N/A 110 7.52 1.62 4.04 3.15N/A 2.48 7.25 4.5 N/A 111 4.63 1.52 4.1 2.01 N/A 1.7 4.78 3.1 N/A 11211.2 1.54 3.99 2.97 N/A 1.83 6.3 4.1 N/A 118 10.1 2.42 5.02 3.85 N/A2.27 8.3 3.4 N/A 120 9.04 4.23 9.27 5.47 N/A 4.35 10.4 2.5 N/A 121 9.423.98 5.48 4.03 N/A 3.71 11 2.8 N/A 122 6.02 1.66 2.02 1.45 N/A 1.31 3.372.0 N/A 123 36.8 4.37 4.32 4.09 N/A 4.18 9.96 2.3 N/A 125 9.57 1.71 5.063.74 4.95 2.5 9.75 5.7 Yes 126 5 3.12 4.05 1.63 N/A 1.44 5.26 1.7 N/A128 42.8 16.9 7.41 21 N/A 9.22 40.8 2.4 N/A 129 66.9 3.98 6.75 4.44 7.054.12 16.5 4.1 Yes 130 7.4 1.57 4.58 3.84 N/A 2.74 10.2 6.5 N/A 131 6.91.46 2.7 1.39 N/A 1.44 2.95 2.0 N/A 132 6.62 1.53 4.05 2.86 N/A 1.949.74 6.4 N/A 133 73 13.1 12.9 15 N/A 12.5 29.6 2.3 N/A 134 23.3 3.946.87 7.22 N/A 4.43 15.6 4.0 N/A 135 19.2 4.89 5.07 4.02 N/A 7.42 8.351.7 N/A 136 9.6 2.95 4.32 4.34 N/A 4.13 8.7 2.9 N/A 137 8.27 4.08 4.324.25 N/A 4.12 10 2.5 N/A 138 7.8 1.43 2.52 1.43 N/A 1.48 3.55 2.5 N/A139 27.8 4.32 4.42 4.8 N/A 4.17 19.5 4.5 N/A 140 21.5 3.37 4.2 4.26 N/A3.93 12.2 3.6 N/A 141 5.01 1.95 4.01 2.39 N/A 2.44 8.13 4.2 N/A 142 44.24.25 6.93 8.72 N/A 10.5 15.1 3.6 N/A 143 7.39 2.14 4.26 3.29 N/A 2.56.39 3.0 N/A 144 8.19 2.17 4.91 4.32 N/A 2.82 9.9 4.6 N/A 145 5.55 3.84.03 7.87 N/A 2.74 21 5.5 N/A 146 38.2 4.53 5.77 12.1 N/A 4.1 26.4 5.8N/A 157 8.03 3.63 2.26 7.6 N/A 2.08 28.2 7.8 N/A 158 5.6 1.48 1.71 1.44N/A 1.32 4.91 3.3 N/A 159 14.3 4.47 5.03 4.13 N/A 4.03 10.2 2.3 N/A 1606.72 1.69 3.92 1.53 N/A 1.55 5.56 3.3 N/A 162 6.95 1.36 2.77 1.5 N/A1.45 2.8 2.1 N/A 163 4.31 0.714 1.38 1 4.48 0.764 2.84 4.0 Yes 164 9.021.52 2.88 3.12 N/A 1.42 9.74 6.4 N/A 165 6.73 1.92 3.08 2.31 N/A 1.444.71 2.5 N/A 166 13.6 3.7 4.16 2.26 N/A 1.47 8.69 2.3 N/A 167 7.56 1.352.76 1.53 N/A 1.26 3.68 2.7 N/A 170 4.69 1.49 1.42 5.31 N/A 1.37 14 9.4N/A 171 6.55 1.34 3.22 3.6 N/A 1.46 9.69 7.2 N/A 172 6.16 1.36 1.55 1.48N/A 1.09 5.53 4.1 N/A 173 7 1.49 2.92 4.1 N/A 1.42 10.3 6.9 N/A 174 6.291.3 1.55 1.61 N/A 1.25 3.2 2.5 N/A 175 7.29 1.42 1.59 3.27 N/A 1.39 6.124.3 N/A 176 5.14 2.4 2.43 4.76 N/A 3 11 4.6 N/A 177 14.9 6.22 4.55 8.99N/A 4.18 20.5 3.3 N/A 180 3.53 0.708 1.48 1.46 2.2 0.958 3.57 5.0 Yes181 4.93 0.734 1.52 1.32 3.11 0.909 4.53 6.2 Yes 182 6.45 1.3 1.28 3.252.07 1.33 11.2 8.6 Yes 183 3.1 1.04 0.796 2.42 3.88 0.7 10.2 9.8 Yes 1845.85 2.58 1.65 5.34 3.67 1.71 27.8 10.8 Yes 185 7.42 3.38 1.01 4.46 2.471.37 13.7 4.1 YES 186 5.5 1.5 2.1 2.3 6.5 1.5 6.8 4.7 YES 187 5.1 2.1 32.7 5.5 1.9 8.1 8.1 YES 229 22.6 4.27 4.63 4.14 N/A 4.33 12.8 3.0 N/A231 27.9 9.27 12 10.6 N/A 4.84 12.3 1.3 N/A 232 13.7 4.13 9.26 2.58 N/A4.14 9.13 2.2 N/A 233 >100 64.3 40.4 62.8 N/A 56.3 48.8 0.8 N/A234 >100 >100 >100 >100 N/A 55.6 >100 n/a N/A 235 >100 69.6 54.4 52.4N/A 48.5 85.8 1.2 N/A 237 >100 66.1 61.3 49.3 N/A 48 94.2 1.4 N/A 2585.42 1.49 3.9 1.49 N/A 1.99 5.91 4.0 N/A

1. A compound of Formula I:

or a pharmaceutically acceptable salt and/or an individual diastereomerthereof, wherein: X═N-J₁,

O, or S; p=0, 1 or 2; q=p or p+1, provided that if p is 0, q does notequal p; R₁, R₂, R₃, and R₄ are each, independently, H, OH, F, Cl, Br,I, CH₃, CF₃, C₂-C₆ straight chain alkyl, substituted C₁-C₆ straightchain alkyl, C₃-C₆ branched alkyl, C₃-C₈ cycloalkyl, allyl, C₂-C₆straight chain alkenyl, substituted C₂-C₆ straight chain alkenyl, C₃-C₆branched alkenyl, C₅-C₈ cycloalkenyl, C₂-C₆ alkynyl, NO₂, CN, NH₂,alkylamine, substituted alkylamine, dialkylamine, arylamine, C(O)NHR₁₄,NHC(O)R₁₅, carbamoyl, aminesulfoxide, sulfonamide, sulfamoyl, sulfonicacid, phenyl, C₅-C₈ aryl, heteroaryl, heterocyclyl, OCH₃, OCF₃, C₂-C₆alkoxy, alkoxycarbonyl, carboxyacid, carbonylalkoxy, SH, thioalkyl,thioaryl, alkylthioaryl, or C₁-C₆ hydroxyl alkyl; J₁ is—(CR₅R₆)_(m)—(CR₇R₈)_(m)—Y, —S(O)_(o)-Z, amidine, substituted amidine,heterocyclyl, substituted heterocyclyl,3,4-dioxo-3,4-dihydronaphthalenyl, heteroaryl, substituted heteroaryl,or

m=0, 1, 2, 3, 4, or 5; n=0, 1, 2, 3,4, or 5; o=1 or 2; t=1 or 2; R₅ andR₆ are each, independently, H, OH, CH₃, CF₃, C₂-C₆ straight chain alkyl,C₃-C₆ branched alkyl, C₃-C₈ cycloalkyl, allyl, C₂-C₆ straight chainalkenyl, C₃-C₆ branched alkenyl, C₅-C₈ cycloalkenyl, C₂-C₆ alkynyl,phenyl, C₅-C₈ aryl, heteroaryl, heterocyclyl, carboxylate, orcarbonylalkoxy; when R₅=R₆, R₅ cannot be OH, NH₂, SH, or NO₂; R₇ and R₈are each, independently, H, F, Cl, Br, I, OH, CH₃, C₂-C₆ straight chainalkyl, CF₃, C₃-C₆ branched alkyl, C₃-C₈ cycloalkyl, C₂-C₆ alkoxy, allyl,C₂-C₆ straight chain alkenyl, C₃-C₆ branched alkenyl, C₅-C₈cycloalkenyl, C₂-C₆ alkynyl, NO₂, CN, amine, alkylamine, dialkylamine,arylamine, carbamoyl, aminesulfoxide, sulfonamide, sulfonic acid,phenyl, C₅-C₈ aryl, heteroaryl, heterocyclyl, OCH₃, OCF₃,alkoxycarbonyl, carboxyacid, carbonylalkoxy, SH, thioalkyl, thioaryl, oralkylthioaryl; when R₇=R₈, R₇ is not OH, NH₂, SH, or NO₂; Y is H, F, Cl,Br, I, CR₁₀═CHR₁₁, CF₃, CH₃, C₂-C₆ straight chain alkyl, substitutedC₂-C₆ straight chain alkyl, C₃-C₆ branched alkyl, CH₂OR₁₆, phenyl,substituted phenyl, C₅-C₈ aryl, substituted C₅-C₈ aryl, C₃-C₈cycloalkyl, substituted C₃-C₈ cycloalkyl, CH₂-heterocycle, C₅-C₈cycloalkenyl, aryloxy, substituted aryloxy, heteroaryl, substitutedheteroaryl, heterocyclyl, substituted heterocyclyl, benzyl, alkylamine,substituted alkylamine, benzylamine, OH, CH₃, CF₃, OCR₁₂═CHR₁₃, C₂-C₆alkynyl, amine, dialkylamine, arylamine, amide, carbamoyl,aminesulfoxide, sulfamide, sulfamoyl, sulfonic acid, heteroaryloxy,OCH₃, OCF₃, C₂-C₆ alkoxy, alkenoxy, phenoxy, benzyloxy, alkoxycarbonyl,carboxyacid, carboxyalkoxy, carbonylalkyl, thio, alkylthio, thioalkyl,arylthio, thioaryl, alkylthioaryl, or

provided that, when n=0 and m=0, Y is H, heterocyclyl, heteroaryl, C₃-C₈cycloalkyl, C₅-C₈ cycloalkyl, aryl, or

each of which may be substituted; if m=n=o, Y is not W is C₂-C₆ straightchain alkyl, substituted C₁-C₆ straight chain alkyl, OCH₃, C₂-C₆ alkoxy,alkylthioalkyl, substituted alkylthioalkyl, C₃-C₈ cycloalkyl,substituted C₃-C₈ cycloalkyl, C₅-C₈ aryl, substituted aryl, phenyl,substituted phenyl, CR₁₀═CHR₁₁, alkylthio, benzyl, substituted benzyl,heterocyclyl, substituted heterocyclyl, phenoxy, aryloxy, substitutedaryloxy, OCR₁₂═CHR₁₃, benzyloxy, heteroaryloxy, substitutedheteroaryloxy, amine, substituted amine, arylamine, substitutedarylamine, phenylamine, substituted phenylamine, CH₃, CF₃, C₃-C₆branched alkyl, C₅-C₈ cycloalkenyl, C₂-C₆ alkynyl, alkylamine,dialkylamine, heteroaryl, CH₂-heterocyclyl, CH₂-substitutedheterocyclyl, OCF₃, alkenoxy, CH₂OR₁₆, thioalkyl, arylthio, thioaryl,alkylthioaryl or alkylcarboxy, phenyl sulfonylamide, or substituted arylsulfonylamide, chlorophenylacetyl; Z is CH₃, CF₃, C₂-C₆ straight chainalkyl, heteroaryl, substituted heteroaryl, phenyl, substituted phenyl,C₅-C₈ aryl, substituted C₅-C₈ aryl, C₃-C₆ branched alkyl, C₃-C₈cycloalkyl, C₅-C₈ cycloalkenyl, C₂-C₆ alkynyl, amine, alkylamine,dialkylamine, arylamine, benzyl, heteroaryloxy, heterocyclyl,CH₂-heterocycle, OCH₃, OCF₃, C₂-C₆ alkoxy, alkenoxy, phenoxy, aryloxy orbenzyloxy; R₉ is H, CH₃, C₂-C₆ straight chain alkyl, or C₃-C₆ branchedalkyl; R₁₀, R₁₁, R₁₂, and R₁₃ are each, independently, H, phenyl, C₅-C₈aryl, CH₃, CF₃, C₂-C₆ straight chain alkyl, C₃-C₈ cycloalkyl,heteroaryl, or heterocyclyl; R₁₄ and R₁₅ are each, independently H,C₂-C₆ straight alkyl, C₃-C₆ branched alkyl, C₃-C₈ cycloalkyl, allyl,C₂-C₆ straight alkenyl, branched alkenyl, C₅-C₈ cycloalkenyl, phenyl,C₅-C₈ aryl, benzyl, CH₂C(OCH₃)₂, heteroaryl, or heterocyclyl; and, R₁₆is C₃-C₆ branched alkyl, C₅-C₈ aryl, substituted C₅-C₈ aryl, heteroaryl,phenyl, substituted phenyl, CH₂-aryl, benzyl, H, CH₃, CF₃, C₂-C₆straight chain alkyl, C₃-C₈ cycloalkyl, heterocyclyl, or CH₂-heteroaryl.J₂ and J₃ are each, independently, H, F, Cl, Br, I, CR₁₇═CHR₁₈, CF₃,CH₃, C₂-C₆ straight chain alkyl, substituted C₁-C₆ straight chain alkyl,C₃-C₆ branched alkyl, CH₂OR₂₁, phenyl, C₅-C₈ aryl, substituted C₅-C₈aryl, C₃-C₈ cycloalkyl, substituted C₃-C₈ cycloalkyl, CH₂-heterocycle,C₅-C₈ cycloalkenyl, aryloxy, substituted aryloxy, heteroaryl,substituted heteroaryl, heterocyclyl, substituted heterocyclyl, benzyl,alkylamine, substituted alkylamine, benzylamine, OH, CH₃, CF₃,OCR₁₉═CHR₂₀, C₂-C₆ alkynyl, amine, dialkylamine, arylamine, amide,carbamoyl, aminesulfoxide, sulfamide, sulfamoyl, sulfonic acid,heteroaryloxy, OCH₃, OCF₃, C₂-C₆ alkoxy, alkenoxy, phenoxy, benzyloxy,alkoxycarbonyl, carboxyacid, carboxyalkoxy, carbonylalkyl, thio,alkylthio, thioalkyl, arylthio, thioaryl, alkylthioaryl, or

when J₂=J₃, J₂ is not OH, NH₂, SH, or NO₂; J₂ and J₃ can form a 4, 5; 6,7, 8 membered spiro ring containing 0, 1, or 2 heteroatoms such as O, N,S; R₁₇, R₁₈, R₁₉, and R₂₀ are each, independently, H, phenyl, C₅-C₈aryl, CH₃, CF₃, C₂-C₆ straight chain alkyl, C₃-C₈ cycloalkyl,heteroaryl, or heterocyclyl; R₂₁ is H, C₂-C₆ straight alkyl, C₃-C₆branched alkyl, C₃-C₈ cycloalkyl, allyl, C₂-C₆ straight alkenyl,branched alkenyl, C₅-C₈ cycloalkenyl, phenyl, C₅-C₈ aryl, benzyl,CH₂C(OCH₃)₂, heteroaryl, or heterocyclyl.
 2. The Compound of claim 1,wherein p=1 and q=1.
 3. The compound of claim 1, wherein p=1 and q=2. 4.The compound of claim 1, wherein p=2 and q=2.
 5. The compound of claim1, wherein p=2 and q=3.
 6. The compound of claim 1, wherein p=0 and q=1.7. The compound of claim 1, wherein R₁, R₂, R₃, and R₄ are each,independently, H, OH, F, Cl, Br, I, CH₃, CF₃, OCH₃, C₂-C₆ alkoxy, C₂-C₆straight chain alkyl, substituted C₂-C₆ straight chain alkyl, phenyl,C₅-C₈ aryl, NO₂, CN, C(O)NHR₁₄ or NHC(O)R₁₅.
 8. The compound of claim 7,wherein R₁, R₂, R₃, and R₄ are each, independently, H, OH, F, Cl, Br, I,CH₃, CF₃, OCH₃, C₂-C₆ alkoxy.
 9. The compound of claim 8, wherein R₁,R₂, R₃, and R₄ are each, independently, H or OCH₃.
 10. The compound ofclaim 9, wherein R₁, R₂ and R₄ are each H and R₃ is OCH₃.
 11. Thecompound of claim 1, wherein X═O or S.
 12. The compound of claim 1,wherein


13. The compound of claim 1, wherein X═N-J₁.
 14. The compound of claim13, wherein J₁ is —(CR₅R₆)_(n)—(CR₇R₈)_(m)—Y
 15. The compound of claim14, wherein n=0 and m=0.
 16. The compound of claim 14, wherein n=1 andm=0.
 17. The compound of claim 14, wherein n=1 and m=1.
 18. The compoundof claim 14, wherein n=1 and m=2.
 19. The compound of claim 14, whereinn=5 and m=5.
 20. The compound of claim 14, wherein R₅ and R₆ are each,independently, H or CH₃.
 21. The compound of claim 14, wherein R₇ and R₈are each, independently, H, F, Cl, Br, I, OH, CH₃, C₂-C₆ straight chainalkyl, CF₃, C₃-C₆ branched alkyl, C₃-C₈ cycloalkyl, or C₂-C₆ alkoxy. 22.The compound of claim 21, wherein R₇ and R₈ are each, independently, Hor OH.
 23. The compound of claim 14, wherein Y is CH₂OR₁₆, phenyl,substituted C₅-C₈ aryl or benzyl.
 24. The compound of claim 16, whereinR₅ and R₆ are each H.
 25. The compound of claim 24, wherein Y issubstituted or unsubstituted C₅-C₈ aryl.
 26. The compound of claim 25,wherein the substituted C₅-C₈ aryl is substituted with from 1 to 5substituents each of which is independently CN, Cl or F.
 27. Thecompound of claim 17, wherein R₅ and R₆ are each H and R₇ and R₈ areeach, independently, H or OH.
 28. The compound of claim 27, wherein Y isCH₂OR₁₆.
 29. The compound of claim 28, where R₁₆ is substituted orunsubstituted C₅-C₈ aryl.
 30. The compound of claim 29, wherein thesubstituted C₅-C₈ aryl is substituted with from 1 to 5 substituents eachof which is independently C₃-C₆ branched alkyl, Cl, or F.
 31. Thecompound of claim 13, wherein J₁ is —S(O)_(o)-Z.
 32. The compound ofclaim 31, wherein o=1.
 33. The compound of claim 31, wherein o=2. 34.The compound of claim 31, wherein Z is CH₃, CF, C₂-C₆ straight chainalkyl, heteroaryl, substituted heteroaryl, phenyl, substituted phenyl,C₅-C₈ aryl, or substituted C₅-C₈ aryl.
 35. The compound of claim 13,wherein J₁ is


36. The compound of claim 35, wherein t=1.
 37. The compound of claim 35,wherein t=2.
 38. The compound of claim 36, wherein W is substitutedaryl, phenyl, phenoxy, aryloxy and substituted aryloxy.
 39. The compoundof claim 38, wherein the aryl and aryloxy is substituted with from 1 to5 substituents each of which is independently CF3 or F.
 40. The compoundof claim 35, wherein t=2 and W is C₂-C₆ alkoxy.
 41. The compound ofclaim 13, wherein R₉ is H.
 42. The compound of claim 13, wherein R₁₀ andR₁₁ are both H.
 43. The compound of claim 13, wherein R₁₂ and R₁₃ areboth H.
 44. The compound of claim 13, wherein R₁₂ is H and R₁₃ isphenyl.
 45. The compound of claim 13, wherein R₁₆ is C₃-C₆ branchedalkyl, C₅-C₈ aryl, substituted C₅-C₈ aryl, heteroaryl, phenyl,substituted phenyl, CH₂-aryl, or benzyl.
 46. The compound of claim 1,which is selected from the following compounds, or a pharmaceuticallyacceptable salt and/or an individual diastereomer thereof:1′-(3-chlorobenzoyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione,1′-(3,4-dichlorobenzoyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione;4-[(5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][2,4]oxathiine-2,4′-piperidine]-1′-yl)methyl]benzonitrile;1′-(2-phenylethyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione;1′-(4-fluorobenzyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione;1′-[3-(4-tert-butylphenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione;1′-(2-hydroxy-3-phenylpropyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]_(j)-5,6-dione;3-(trifluoromethyl)phenyl5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylate;4-fluorophenyl5,6-dioxo-5,6-dihydro-1′H-spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-1′-carboxylate;1′-(2-chloro-6-fluorobenzyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione;1′-(3-chloro-4-fluorobenzyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione;1′-(3-phenoxypropyl)spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione;1′-[2-(4-chlorophenoxy)ethyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione;1′-[(2S)-3-(4-fluorophenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione;1′-[(2S)-3-(4-tert-butylphenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione;1′-[(2R)-3-(4-tert-butylphenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione;1′-[(2R)-3-(4-fluorophenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione;1′-[(2S)-3-(4-chlorophenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione;1′-[(2R)-3-(4-chlorophenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione;1′-[(2R)-2-hydroxy-3-phenylpropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione;1′-[(2S)-2-hydroxy-3-phenylpropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione:1′-[(2S)-2-hydroxy-3-(2-methylphenoxy)propyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione;1′-isopropylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione:1′-[(2S)-3-(4-ethylphenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione;1′-[(2R)-3-(4-ethylphenoxy)-2-hydroxypropyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione;and1′-[(2R)-2-hydroxy-3-(2-methylphenoxy)propyl]spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione.47. A pharmaceutical composition comprising a compound of claim 1 incombination with a pharmaceutically acceptable carrier or excipient. 48.The pharmaceutical composition of claim 47 further comprising a secondchemotherapeutic agent.
 49. The pharmaceutical composition of 48,wherein said second chemotherapeutic agent is selected from the groupconsisting of tamoxifen, raloxifene, anastrozole, exemestane, letrozole,cisplatin, carboplatin, paclitaxel, cyclophosphamide, lovastatin,minosine, gemcitabine, araC, 5-fluorouracil, methotrexate, docetaxel,goserelin, vincristin, vinblastin, nocodazole, teniposide, etoposide,epothilone, navelbine, camptothecin, daunonibicin, dactinomycin,mitoxantrone, amsacrine, doxorubicin, epirubicin, idarubicin imatanib,gefitinib, erlotinib, sorafenib, sunitinib malate, trastuzumab,rituximab, cetuximab, and bevacizumab.
 50. A method of treating a cellproliferative disorder, said method comprising administering to asubject in need thereof a therapeutically effective amount of a compoundof formula I as defined in claim 1, or a pharmaceutically acceptablesalt thereof, or a prodrug or metabolite thereof, in combination with apharmaceutically acceptable carrier, wherein said cell proliferativedisorder is treated.
 51. The method of claim 50, wherein said cellproliferative disorder is a precancerous condition.
 52. The method ofclaim 50, wherein said cell proliferative disorder is a cancer.
 53. Themethod of claim 50, wherein said cancer is adenocarcinoma, squamouscarcinoma, sarcoma, lymphoma, multiple myeloma, or leukemia.
 54. Themethod of claim 50, wherein said cancer is lung cancer, colon cancer,breast cancer, pancreatic cancer, prostate cancer, acute leukemia,chronic leukemia, multiple melanoma, ovarian cancer, malignant glioma,leiomyosarcoma, hepatoma, or head and neck cancer.
 55. The method ofclaim 50, wherein said compound of formula I, or a pharmaceuticallyacceptable salt thereof, or a prodrug or metabolite thereof, isadministered in combination with a second chemotherapeutic agent. 56.The method of claim 55, wherein said second chemotherapeutic agent isselected from the group consisting of tamoxifen, raloxifene,anastrozole, exemestane, letrozole, cisplatin, carboplatin, paclitaxel,cyclophosphamide, lovastatin, minosine, gemcitabine, araC,5-fluorouracil, methotrexate, docetaxel, goserelin, vincristin,vinblastin, nocodazole, teniposide, etoposide, epothilone, navelbine,camptothecin, daunonibicin, dactinomycin, mitoxantrone, amsacrine,doxorubicin, epirubicin, idarubicin imatanib, gefitinib, erlotinib,sorafenib, sunitinib malate, trastuzumab, rituximab, cetuximab, andbevacizumab.
 57. The method of claim 50, wherein said treating cancercomprises a reduction in tumor size, a delay of tumor growth, animprovement in the survival of patients, or an improvement in thequality of patient life.
 58. The method of claim 50, wherein the canceris primary cancer or metastatic cancer.